CN101657436A - Macrocyclic ghrelin receptor modulators and using method thereof - Google Patents

Macrocyclic ghrelin receptor modulators and using method thereof Download PDF

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CN101657436A
CN101657436A CN200880010587A CN200880010587A CN101657436A CN 101657436 A CN101657436 A CN 101657436A CN 200880010587 A CN200880010587 A CN 200880010587A CN 200880010587 A CN200880010587 A CN 200880010587A CN 101657436 A CN101657436 A CN 101657436A
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forming
low alkyl
alkyl group
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H·霍维达
G·弗拉泽
S·博歇明
M·布拉萨
D·德鲁茨
E·马索尔特
L·厄勒特
M·L·彼得森
Z·王
K·贝纳克利
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Tranzyme Pharma Inc
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Abstract

The invention provides the macrocylc compound that novel conformation is determined, this macrocylc compound can play the selective modulator of ghrelin receptor (secretagogue receptor, GHS-R1a and hypotype thereof, isotype and variant).The present invention has also described the method for synthetic this novel cpd.These compounds are as the agonist of ghrelin receptor and as treating and preventing the medicine of a series of medical disorder, described medical disorder to include but not limited to metabolism and/or endocrine disorder, gastrointestinal disorder, cardiovascular disorder, obesity and obesity associated conditions, central nervous system disorders, osteopathy, hereditary illness, hyper-proliferative illness and inflammatory conditions.

Description

Macrocyclic ghrelin receptor modulators and using method thereof
Related application data
The application requires the rights and interests of the U.S. Patent Application Serial Number 60/889,163 of submission on February 9th, 2007, and its disclosure is incorporated in this integral body by reference.
Invention field
The present invention relates to the macrocylc compound that novel conformation is determined, this macrocylc compound is incorporated into ghrelin (growth hormone cinogenic agent) acceptor and/or is the function regulator of ghrelin (growth hormone cinogenic agent) acceptor, and described acceptor comprises GHS-R1a and hypotype, isotype and/or variant.The invention still further relates to the intermediate of these compounds, the method that contains the pharmaceutical composition of these compounds and use this compound.These novel macrocylc compound are as the treatment of a series of disease indications.Specifically, these compounds are used for the treatment of and prevent gastrointestinal disorder, include but not limited to postoperative ileus, gastroparesis (comprising diabetic gastroparesis), OPIOIDS intestinal dysfunction (opioidbowel dysfunction), chronic intestinal pseudo-obstruction, short bowel syndrome and functional gastrointestinal illness.In addition, this compound has the application of treatment and prevention metabolism and/or endocrine disorder, cardiovascular disorder, obesity and obesity associated conditions, central nervous system disorders, osteopathy, hereditary illness, hyper-proliferative illness and inflammatory conditions.
Background of invention
By the research work aspect genomics and the proteomics the raising of promoted understanding to various physiological regulation approach begun to influence the exploitation of pharmaceutical preparations.Specifically, the discriminating to key receptor and their endogenous ligands has been that these receptor/ligand of exploitation are to having created new opportunity as the treatment target.For example, ghrelin is 28 amino acid peptide parahormones that characterize recently, and it separates from the stomach of rat at first, with in the people, differentiate subsequently have lineal homology (Kojima, a M.; Hosoda, people Nature 1999,402 such as H., 656-660.) to exist this peptide to show that it plays a part in many other species in the normal body function conservative and important.This peptide has proved previous orphan's g protein coupled receptor (GPCR), mainly be found in 1 type growth hormone cinogenic agent (secretatogue) acceptor (hGHS-R1a) (Howard, A.D. of brain (arcuate nucleus in hypothalamus, hippocampus and the black substance and ventromedial nucleus) and hypophysis; Feighner, S.D.; Deng people Science 1996,273, endogenous ligands 974-977).(United States Patent (USP) the 6th, 242, No. 199; International patent application no WO 97/21730 and WO 97/22004) recognize the endogenous ligands of hGHS-R1a, it has been re-classified as ghrelin receptor (GHRN) (Davenport recently, A.P. wait people Pharmacol.Rev.2005,57,541-546).Also central nervous system (CNS) other the zone and peripheral tissues's (for example suprarenal gland and Tiroidina, heart, lung, kidney and skeletal muscle) in detect this receptor.This receptor separate and characterize endogenous peptide part before cloned by discriminated union, and it with relate to adjusting tethelin (GH) excretory other acceptors, particularly tethelin-releasing hormone (GHRH) acceptor difference.
The exclusive feature of rat and people's peptide is at Ser 3On have positive decoyl (Oct) part.Yet, in circulation, go the acyl group form to preponderate, about 90% hormone is this form.This group is derived from posttranslational modification, and show relevant with biological activity, and may be also be transported to CNS relevant (Banks, W.A.;
Figure G2008800105877D00021
M.; Robinson, S.M.; Heiman, M.L.J.Pharmacol.Exp.Ther.2002,302,822-827.)。In GH-discharge to measure, the effectiveness of hormone of going the decoyl form was than low at least 100 times of parent peptide, may be some the reason that causes in the other biological effect relevant with ghrelin although shown the acyl group species.This to go the acyl group form to be assumed to be the reason that mainly causes owing to the cardiovascular and cell propagation effect of ghrelin, and the acidylate form participates in keeping energy balance and tethelin discharges.(Baldanzi, G.; Filighenddu, N.; Cutrupi, people J.Cell Biol.2002 such as S., 159,1029-1037.) similarly, remove Gln 14The derivative of-ghrelin and decoylization thereof is separated with the endogenous form of hormone, and described hormone is produced by the alternative splicing of ghrelin gene, but finds that both stimulate GH release aspect non-activity in vivo.(Hosoda，H.；Kojima，M.；Matsuo，H.；Kangawa，K..J.Biol.Chem.2000，275，21995-2120。) in blood plasma, observed other less important forms by the translation ghrelin that post-treatment produced, although there is not special activity owing to them.(Hosoda, H.; Kojima, people J.Biol.Chem.2003 such as M., 278,64-70.)`
Even before separating this acceptor and its endogenous peptide part, big quantity research has been devoted to seek can stimulate GH excretory medicament.The suitable adjustable of people GH not only to suitable physical growth, and had importance to a series of other important physiological effects.Because GH and other GH stimulator polypeptides, such as GHRH and somatotropin releasing factor (GRF), and their derivative and analogue are to use via injection, in order to utilize these positive effects better, to concentrate on exploitation can increase GH excretory Orally active therapeutical agent, is called GH secretogogue (GHS).In addition, expect that the pulsed physiology that GH is more closely simulated in the use of these medicinal preparation for oral administration discharges.
Since the discriminating of phase late 1970s growth hormone-releasing peptide (GHRP) (Bowers, C.Y.Curr.Opin.Endocrinol.Diabetes 2000,7,168-174; Camanni, F.; Ghigo, E.; Arvat, E.Front.Neurosci.1998,19,47-72; Locatelli, V.; Torsello, A..Pharmacol.Res.1997,36,415-423), studied the potentiality of a large amount of medicaments as GHS.Stimulation that GH is discharged except them and the positive effect of following in this regard, estimated that GHS has effectiveness in treatment in multiple other illnesss, described illness is included in the apocleisis that observed expendable illness (wasting condition) (emaciation) and cancer cause among the HIV/AIDS patient, the elderly's flesh bone fragility and growth hormone deficiency disease.Many effort in past 25 years have produced many GHS that effectively can be oral.(Rocha-Sousa, A.; Henriques-Coelho, T.; Leite_Moreira, A.F.Exp.Opin.Ther.Patents 2007,17,909-926; Isidro, M.L.; Cordido, F.Comb.Chem.High Throughput Screen.2006,9,178-180; Smith, R.G.; Sun, Y.X.; Beatancourt, L.; Asnicar, M.Best Pract.Res.Clin.Endocrinol.Metab.2004,18,333-347; Fehrentz, J.-A.; Martinez, J.; Boeglin, D.; Guerlavais, V.; Deghenghi, R.IDrugs 2002,5,804-814; Svensson, J.Exp.Opin.Ther.Patents 2000,10,1071-1080; Nargund, R.P.; Patchett, people such as A.A..J.Med.Chem.1998,41,3103-3127; Ghigo, E; Arvat, E.; Camanni, F.Ann.Med.1998,30,159-168; Smith, R.G.; Van der Ploeg, L.H.T.; Howard, A.D.; Feighner, people Endocr.Rev.1997 such as S.D., 18,621-645.) these comprise little peptide (such as sea sand Rayleigh (Zentaris) and ipamorelin (NovoNordisk)), and neplanocin, and small molecules such as capromorelin (Pfizer), L-252,564 (Merck), MK-0677 (Merck), NN703 (tabimorelin, Novo Nordisk), G-7203 (Genentech), S-37435 (Kaken) and SM-130868 (Sumitomo), BMS-604992 (Bristol-Myers Squibb) and RC-1291 (anamorelin, Sapphire), they are designed to have the Orally active of stimulating growth hormone.Yet, the clinical trial of these medicaments provides disappointed result, this is because except other aspects, the effectiveness in it lacks during the treatment that prolongs or the side effect of non-expectation is arranged, and described side effect comprises and irreversibly suppresses cytochrome P 450 enzymes (Zdravkovic M.; Olse, A.K.; Christiansen, people Eur.J.Clin.Pharmacol.2003 such as T., 58,683-688.)。Therefore, still need to be the therapeutic action medicament of target ghrelin receptor effectively.
Though ghrelin relates to the adjusting of GH, it is mainly synthetic secreting in the acid gland of stomach, although it also comprises kidney, pancreas and hypothalamic other organs (Kojima, M. certainly with less volume production; Hsoda, H.; Kangawa, K.Horm.Res.2001,56 (supplementary issues 1), 93-97; Ariyasu, H.; Takaya, K.; Tagami, T. wait people Stomach is a major source of circulatingghrelin, and feeding state determines plasma ghrelin-like immunoreactivitylevels in humans (stomach is the main source of the plain release peptide of cycling deposition, and feeding state decider's blood plasma ghrelin sample immunoreactivity level).J.Clin.Endocrinol.Metab.2001，86，4753-4758。)。Except its stimulating GH effect in discharging, this hormone has multiple other internal secretion and non-endocrine function (Broglio, F.; Gottero, C.; Arvat, E.; Ghigo, E.Horm.Res.2003,59,109-117), and shown in keeping suitable energy balance with many other physiological systems and interacted.(Horvath，T.L.；Diano，S.；Sotonyi，P.；Heiman，M.；
Figure G2008800105877D00041
M.Endocrinology?2001，142，4163-4169；Casanueva，F.F.；Dieguez，C.Rev.Endocrinol.Metab.Disord.2002，3，325-338)。Especially, ghrelin plays appetizing signal (orexigenicsignal) in control is ingested, and wherein it is used to offset the influence of Leptin.In fact, it is to be proved to be first kind of intestines peptide with this appetizing character.(Kojima，M.；Kangawa，K.Curr.Opin.Pharmacology?2002，2，665-668。) this hormone also involves hypothalamus and regulate many synthetic and secretions that relate to other neuropeptides of appetite and feeding behavior.Response fasting or the restriction of persistent food, level rising (Nakazato, the M. of ghrelin; Murakami, N.; Date, Y.; Kojima, people Nature 2001,409 such as M., 194-198.).For example, suffer from apocleisis or bulimiac curee and show the rising of ghrelin level.Found preceding on the feed rising of cyclical level of this hormone, and the back reduces on the feed.In addition, the weight saving of diet induced causes the rising of ghrelin level, although carry out stomach change its course the operation obesity the curee not equally ground warp be subjected to this rising.(Cummings, D.E.; Weigle, D.S.; Frayo, people N.Engl.J.Med.2002 such as R.S., 346,1623-1630)
The substantial connection of ghrelin and control ingestion of food and appetite makes it to become the attractive target of obesity research.(Spanswick，D.；Lee，K.Exp.Opin.Emerging?Drugs2003，8，217-237；Horvath，T.L.；
Figure G2008800105877D00051
T.；Tang-Christensen，M.；Pagotto，U.；
Figure G2008800105877D00052
M.H.Curr.Pharm.Design?2003，9，1383-1395；Crowley，V.E.F.；Yeo，G.S.H.；O-Rahilly，S.Nat.Rev.Drug?Disc.2002，1，276-286。) in fact, other crude substance of minority have been proved to be the adjusting that participates in GH secretion and ingestion of food.
Similarly, ghrelin works in regulating Regular Insulin release and glucemia, and therefore the conditioning agent of ghrelin receptor has application (Yada, the T. that treats diabetes and metabolism syndrome; Dezaki, K.Sone, people Curr.Diab.Rev.2008 such as H., 4,18-23).
In addition, as previously mentioned about GHS, proved that ghrelin and ghrelin agonist have positive effect in expendable syndrome and emaciation.Start clinical trial and utilized these effects.(Strasser，F.；Lutz，T.A.；Maeder，M.T.Br.J.Cancer?2008，98，300-308；Garcia，J.M.；Polvino，W.J.The?Oncologist?2007，12，594-600。)
The other effect of the ghrelin of also not developing that is used for the treatment of purpose is to regulate stomach motion and gastric acid secretion so far.Motivator activity (pro-kinetic activity) shows with the GH secretion irrelevant, and may be walked by the fan-cholinergic muscarine approach (vagal-cholinergic muscarinicpathway) mediation (mediate).Required dosage level equals the GH and the required level of appetite stimulation effect of hormone.Notably be and to remove Gln 14Peptide is compared other effect non-activities of ghrelin, has proved Gln 14Peptide also promotes motion.(Chen, C.-Y.; Inui, A.; Asakawa, A.; Fujino, K.; Kato, I.; Chen, C.-C.; Ueno, N.; Fujimiya, M.Gastroenterology 2005,129,8-25; Chen, C.-Y.; Chao, Y; Chang, F.-Y.; Chien, E.J.; Lee, S.-D.; Doong, M.-L.Int.J.Mol.Med.2005,16,695-699; Trudel, L.; Bouin, M.; Tomasetto, C.; Eberling, P.; St-Pierre, S.; Bannon, P.; L ' Heureux, M.C.; Poitras, P.Peptides 2003,24,531-534; Trudel, L.; Tomasetto, C.; Rio, M.C.; Bouin, M.; Plourde, V.; Eberling, P.; Poitras, P.Am.J.Physiol.2002,282, G948-G952; Peeters, T.L.J.Physiol.Pharmacol.2003,54 (supplementary issues 4), 95-103.)
More and more evidences has confirmed that ghrelin is the conditioning agent of inflammation and immunologic function.(Taub，D.D.Vitamins?and?Hormones?2007，77，325-346；Vixit，V.D.；Taub，D.D.Exp.Gerontol.2005，40，900-910。) ghrelin suppresses expression (Dixit, the V.D. of the pro-inflammatory cytokine (such as IL-1 β, IL-6 and TNF-α) in person monocytic cell and the T cell especially; Schaffer, people J.Clin.Invest.2004 such as E.M., 114,57-66).Ghrelin shows the anti-inflammatory action that makes new advances by the inactivation of NF-kB pathway in human endothelial cell.(Li, W.G.; Gavrila, D.; Liu, people Circulation 2004,109 such as X., 2221-2226; Zhao, D.; Zhan, Y.; Zeng, people J.Cell.Biochem.2006 such as H., 97,1317-1327.)。Ghrelin applies protective effect to the gastric mucosa that partly mediates by prostaglandin(PG).(Konturek, P.C.; Brzozowski, T.; Pajdo, people J.Physiol.Pharmacol.2004 such as R., 55,325-336.) at IBD (Peracchi, M.; Bardella, people Gut 2006,55 such as M.T., 432-433; Karmiris, K.; Koutroubakis, people Inflamm.Bowel Dis.2006 such as I.E., 12,100-105), colitis (Gonzalez-Re y, E.; Chorny, A.; Delgado, M.Gastroenterology 2006,130,1707-1720), peptic ulcer disease (Suzuki, H.; Masaoka, T.; Nomoto, people Aliment.Pharmacol.Ther.Symp.Ser.2006 such as Y., 2,120-126), duodenal ulcer (Fukuhara, S.; Suzuki, H.; Masaoka, people Am.J.Physiol.2004 such as T., 289, G 138-G145) and postoperative abdomen interior Sepsis (Maruna, P.; G ü rlich, R.; Frasko, R.; Rosicka, M.Eur.Surg.Res.2005,37, among patient 354-359), the ghrelin level raises, but at rheumatoid arthritis (Otero, M.; Nogueiras, people Rheumatol.2004 such as R., 43,306-310) middle ghrelin level reduces.In rat model, ghrelin prevents or improves ischemia reperfusion injury (Konturek, P.C.; Brzozowski, people Eur.J.Pharmacol.2006 such as T., 536,171-181), damage (Kasimay, the O. of pancreas and liver; Iseri, S.O.; Barlas, people Hepatol.Res.2006 such as A., 36,11-19), acute pancreatitis (Dembinski, A.; Warzecha, people J.Physiol.Pharmacol.2003 such as Z., 54,561-573), Sepsis and septic shock (Wu, R.; Dong, W.; Cui, people Ann.Surg.2007 such as X., 245,480-486; Chang, L.; Lu, people Acta Pharmacol.Sin.2003 such as J.-B., 24,45-49), the gastric injury (Iseri, the S. that cause by some drugs; Sener, people J.Endocrinol.2005 such as G., 187,399-406), irritability (stress-induced) gastric injury (Brzozowski, T.; Konturek, P.C.; Konturek, people Regul.Pept.2004 such as S.J., 120,39-51), helicobacter pylori (H.pylori) gastric injury (Isomoto, the H. that cause; Ueno, people Dig.Dis.Sci.2005 such as H., 50,833-838) and inflammatory pain (Sibilia, V.; Lattuada, people Neuropharmacology 2006,51 such as N., 497-505).Ghrelin also relevant (Stenvinkel, P. with chronic nephropathy; Pecoits-Filho, R.; Lindholm, B.Adv.Renal ReplacementTher.2003,10,332-3450).In addition, confirmed peptide agonists in animal model effectively, be included in the rat GHRP-2 to sacroiliitis (Granado, M.; Priego, people Am.J.Physiol.2005 such as T., 288, E486-E492; Am.J.Physiol.2005,289, E1007), and in dog GHRP-6 to acute ischemia.(Shen，Y.-T.；Lynch，J.J.；Hargreaves，R.J.；Gould，R.J.J.Pharmacol.Exp.Ther.2003，306，815-820。) therefore, ghrelin and ghrelin agonist can be used for treatment and prevention of inflammatory conditions.Be that the ghrelin antagonist has been described and has been used for the treatment of enteritis (U.S. Patent Application Publication 200710025991) enjoyably.
Ghrelin also involves all respects of reproduction and neonatal development.(Arvat, E.; Gianotti, L.; Giordano, people Endocrine 2001,14 such as R., 35-43.) cardiovascular effect of ghrelin also is important, because this peptide is powerful vasodilator.With regard to this point, the ghrelin agonist has the potentiality of chronic heart failure.(Nagaya, N.; Kangawa, K.Regul.Pept.2003,114,71-77; Nagaya, N.; Kangawa, K.Curr.Opin.Pharmacol.2003,3,146-151; Bedendi, I.; Alloatti, G.; Marcantoni, A.; Malan, D.; Catapano, F.; Gh é, people Eur.J.Pharmacol.2003 such as C., 476,87-95; Isgaard, J.; Johansson, I.J.Endocrinol.Invest.2005,28,838-842.) international application published WO 2004/014412 described the purposes that the ghrelin agonist protects necrocytosis in the myocardial cell and treatment causes illness in heart failure as heart protective agent.
Ghrelin also involves the adjusting of bone metabolism.(van der Velde, M.; Delhanty, people Vitamins and Hormones 2008,77 such as P., 239-258).Ghrelin and acceptor GHS-R1a thereof are differentiated in scleroblast, and ghrelin promotes propagation and differentiation.In addition, in rat, ghrelin increases bone mineral density, and directly influences bone forming.(Fukushima, N.; Hanada, R.; Teranishi, people J.Bone Mineral Res.2005 such as H., 20,790-798).
In addition, proved that ghrelin has the effective retarding effect that in vitro and in vivo blood vessel is taken place.(Baiguera, S.; Conconi, M.T.; Guidolin, people Int.J.Mol.Med.2004 such as D., 14,849-854; Conconi, M.T.; Nico, B.; Guidolin, people Peptides2004 such as D., 25,2179-2185.)
In addition, also having obtained ghrelin may involve anxiety and other CNS illnesss and improve the evidence of remembering.(Carlini, V.P., Monzon, M.E., Varas, MM., Cragnolini, A.B., Schioth, H.B., Scimonelli, T.N., de Barioglio, S.R.Biochem.Biophys.Res.Commun.2002,299,739-743; Diano, S.; Farr, S.A.; Benoit, people Nature Neurosci.2006 such as S.C., 9,381-388; McNay, E.C.Curr.Opin.Pharmacol.2007,7,628-632.) last, prove that also ghrelin has the effect of the sleep regulated.(Szentirmai，E.；Kapás，L.；Krueger，J.M.Am.J.Physiol.Regul.Integr.Comp.Physiol.2007，292，R575-R585；Szentirmai，E.；Hajdu，I.；Obal，Jr，F.；Krueger，J.M.Brain?Res.2006，1088，131-140；Yannielli，P.C.；Molyneux，P.C.；Harrington，M.E.；Golombek，D.A.J.Neurosci.2007，2890-2895；Tolle，V.；Bassant，M.-H.；Zizzari，P.Endocrinology?2002，143，1353-1361。Yet), the sleep-wake cycle of having reported the ghrelin knock-out mice is normal, shows that the adjusting situation may be complicated more.(Szentirmai, E.; Kap á s, people Am.J.Physiol.Regul.Integr.Comp.Physiol.2007 such as L., 293, R510-R517.) therefore, the ghrelin agonist is used to prevent or improve the illness that relates to CNS as treatment, comprises anxiety, anxiety, the cognitive enhancing and the sleep adjusting.
GHS, ghrelin and other peptides have been discussed respectively for WO 2005/097174 and WO 2006/045314 or it is combined in the purposes for the treatment of in emaciation and the chronic obstructive pulmonary disease.WO2005/09726 has reported that GHS is used for the treatment of the disease that is caused by the C-reactive protein.WO2006/045319 has described the purposes of GHS in treatment kidney and/or liver failure and complication thereof.More generally, WO 2005/097173 shows that GHS lacks at the treatment ghrelin, comprises the purposes in the wide range of therapeutic indication.
A large amount of influences of ghrelin have illustrated the hypotype that has its acceptor in the people, although also do not differentiate.(Torsello, A.; Locatelli, Y.; Melis, M.R.; Succu, S.; Spano, M.S.; Deghenghi, R.; Muller, E.E.; Argiolas, A.; Torsello, A.; Locatelli, people Neuroendocrinology 2000,72 such as V., 327-332.Yet) in initial token, separate and identify the GHS-R1a of the inactive form of brachymemma, be called GHS-R1b.Other receptor subtype may be present in different tissues and explain that the evidence of the Different Effects that is shown by endogenous peptide and synthetic GHS increases.For example, also in breast cancer cell line, myocardial cell and guinea pig heart, found ghrelin and removed the high affine binding site of acyl group ghrelin that they relate to antiproliferative, Cardioprotective and the negativity heart variable force effect that mediates peptide.Similarly, in prostate cancer cell, also found specific GHS binding site outside GHS-R1a and the GHS-R1b.In addition, ghrelin with go the acyl group ghrelin that the cell proliferation in the prostate cancer cell line is applied different influences.(Cassoni, P.; Gh é, C.; Marrocco, people E Eur.J.Endocrinol.2004 such as T., 150,173-184.) then, these different receptor subtypes can involve the wide biological activity that is shown by endogenous peptide and synthetic GHS independently.In fact, recently, the existence of receptor subtype is provided to explain that ghrelin promotes the fat accumulation, although it stimulates lipolytic hormone, tethelin effectively.(Thompson，N.M.；Gill，D.A.S.；Davies，R.；Loveridge，N.；Houston，P.A.；Robinson，I.C.A.F.；Wells，T.Endocrinology?2004，145，234-242。) in addition, bright ghrelin generation of this worksheet and the ratio of going the acyl group ghrelin to generate can respond the balance between nutritional status auxiliary adjustment steatogenesis and the steatolysis.
Success generation peptide class analogs of ghrelin provides powerful evidence for the existence and the physiological correlations of other receptor subtypes, and increase separates with the effect of appetite described analogue with the GH adjusting effect of ghrelin and to weight.(Halem，H.A.；Taylor，J.E.；Dong，J.Z.；Shen，Y.；Datta，R.；Abizaid，A，；Diano，S.；Horvath，T.L.；Culler，M.D.Neuroendocrinol.2005，81，339-349；Halem，H.A.；Taylor，J.E.；Dong，J.Z.；Shen，Y.；Datta，R.；Abizaid，A.；Diano，S.；Horvath，T.；Zizzari，P.；Bluet-Pajot，M.-T.；Epelbaum，J.；Culler，M.D.Eur.J.Endocrinol.2004，151，S71-S75。) BIM-28163 plays the GHS-R1a receptor antagonist, and inhibition is by the receptor activation of natural auxin release peptide.Yet this same molecule is about stimulating the full agonist of weight increase and ingestion of food.In addition, according to the combination research in the different tissues that demonstrates the difference between peptide class GHS and the non-peptide GHS, proposed to still have the receptor subtype that does not characterize to exist.(Ong，H.；Menicoll，N.；Escher，F.；Collu，R.；Deghenghi，R.；Locatelli，V.；Ghigo，E.；Muccioli，G.；Boghen，M.；Nilsson，M.Endocrinology?1998，139，432-435。) reported in rat testicle the difference between the expression of total GHS-R expression and GHS-R1a hypotype.(Barreiro，M.L.；Suominen，J.S.；Gaytan，F.；Pinilla，L.；Chopin，L.K.；Casanueva，F.F.；Dieguez，C.；Aguilar，E.；Toppari，J.；Tena-Sempere，M.Biol.Reproduction?2003，68，1631-1640。) the GHS-R hypotype on the cholinergic nerve is assumed to observed ghrelin and peptide class GHS during the combination research of the motilin receptor the explanation of the not same-action of neural contractile response.(Depoortere，I.；Thijs，T.；Thielemans，L.；Robberecht，P.；Peeters，T.L.J.Pharmacol.Exp.Ther.2003，305，660-667。) last, WO2006/009645 has reported that with WO 2006/009674 use Macrocyclic ghrelin agonist separates the GI effect with the GH release effects in animal model, show that also different hypotypes relates to these physiological effects.
The various active relevant with ghrelin receptor also may be because the different different signal transduction paths of agonist activation, and shown in ghrelin and adenosine, their boths interact as the agonist of GHS-R1a.(Carreira，M.C.；Camina，J.P.；Smith，R.G.；Casanueva，F.F.Neuroendocrinology?2004，79，13-25。)
The functionally active that has shown GPCR often need form dimer or other polymer complex body with himself or other protein.(Prinster, S.C.; Hague, C.; Hall, R.A.Pharmacol.Rev.2005,57,289-298; Park, P.S.; Filipek, S.; Wells, J.W.; Palczewski, K.Biochemistry 2004,43,15643-15656; Rios, C.D.; Jordan, B.A.; Gomes, I.; Devi, the L.A.G-protein-coupled receptor dimerization:modulation ofreceptor function. (dimerisation of g protein coupled receptor: the adjusting of function of receptors) Pharmacol.Ther.2001,92,71-87; Devi, L.A.Trends Pharmacol.Sci.2001,22,532-537.) similarly, the activity of ghrelin receptor also may be at least in part by these complex body control.For example, some report shows interaction (Cunha, the S.R. of GHS-R1a and GHRH; Mayo, K.E.Endocrinology 2002,143,4570-4582; Malag ó n, M.M.; Luque, R.M.; Ruiz-Guerrero, E.; Rodriguez-Pacheco, F.; Garcia-Navarro, S.; Casanueva, F.F.; Gracia-Navarro, F.;
Figure G2008800105877D00101
J.P.Endocrinology 2003,144,5372-5380) or the interaction between the receptor subtype (Chan, C.B.; Cheng, C.H.K.Mol.Cell.Endocrinol.2004,214,81-95) may relate to the function of regulating this receptor.
In addition, with the appetite stimulator effect of ghrelin constitutive activity owing to this receptor.(Holst，B.Schwartz，T.J.Clin.Invest.2006，116，637-641；Holst，B.；Schwartz，T.W.Trends?Pharmacol.Sci.2004，25，113-117；Holst，B.；Holliday，N.D.；Bach，A.；Elling，C.E.；Cox，H.M.；Schwartz，T.W.J.Biol.Chem.2004，279，53806-53817；Holst，B.；Cygankiewicz，A.；Jensen，T.H.；Ankersen，M.；Schwartz，T.W.Mol.Endocrinol.2003，17，2201-221。) recently observed people with the ghrelin receptor sudden change that has damaged constitutive activity is of short and small stature showing, constitutive activity is to the importance of normal function in the body of this receptor.(Pantel, J.; Legendre, M.Cabrol, people J.Clin.Invest.2006 such as S., 116,760-768.)
The exploitation ghrelin receptor of having reported is used for the treatment of the overwhelming majority in the method for purpose and concentrates on and regulate metabolic function.Similarly, concentrating on about the overwhelming majority in the document of GHS can be via the illness of its GH promoter action treatment.Especially, embodiments more of the present invention described herein are utilized the selectively activate of ghrelin receptor, for treatment is that the disease of feature provides approach with the GI dyskinesia.The observed GI proof from motion ghrelin agonist that improves with ghrelin can be used for revising and hypokinesis or limited relevant illness.(Murray，C.D.R.；Kamm，M.A.；Bloom，S.R.；Emmanuel，A.V.Gastroenterology2003，125，1492-1502；Fujino，K.；Inui，A.；Asakawa，A.；Kihara，N.；Fujimura，M.；Fujimiya，M.J.Physiol.2003，550，227-240；Edholm，T.；Levin，F.；
Figure G2008800105877D00111
P.M.；Schmidt，P.T.Regul.Pept.2004，121，25-30；Locatelli，V.；Bresciani，E.；Bulgarelli，I.；Rapetti，D.；Torsello，A.；Rindi，G.；Sibilia，V.Netti，C.J.Endocrinol.Invest.2005，28，843-848；Peeters，T.L.Gut?2005，54，1638-1649；Fruhwald，S.；Holzer，P.；Metzler，H.Wien.Klin.Wochenschr.2008，120，6-17。)
These illness comprise postoperative ileus.(POI，Luckey，A.；Livingston，E.；Taché，Y.Arch.Surg.2003，138，206-214；Baig，M.K.；Wexner，S.D.Dis.ColonRectum?2004，47，516-526；Greewood-Van?Meerveld，B.Exp.Opin.EmergingDrugs?2007，12，619-627；Senagore，A.J.Am.J.Health?Syst.Pharm.2007，64，S3-S7；Maron，D.J.；Fry，R.D.Am.J.Ther.2008，15，59-65。) POI is defined as the damage of the GI motion that usually occurs in after abdominal operation, intestinal surgery, gynecilogical operation and the operation on pelvis.Only in the U.S., annual 2100000 operations cause POI, cause surpassing 1,000,000,000 dollars economic impact.Think that POI is the harmful response with operation technique of the general variable duration that continues 72 hours.It is characterized by pain, abdominal tympanites or swelling, nausea and vomiting, gas and fluid gathers in intestines and postpones defaecation.The patient promptly is impatient at oral feed, does not also have defecation, up to intestinal function recovery.POI causes many consequences of not expecting, comprises the increase of patient's sickness rate, expensive hospital stay prolong and, in addition, its major cause for being admitted to hospital once more.In addition, the opiate medicine that the operation back provides as analgesic agent has increased the weight of this illness, and this is because the side effect of the inhibition intestinal function that they are generally acknowledged.
The operation technique of stomach or intestines causes the disintegration of intestines-brain signal pathway, has damaged the GI activity and has triggered POI.Ghrelin local action under one's belt is confused afferent neuron (vagal afferent neurons) discharge to stimulate and to coordinate, and therefore regulates bowel movement.Therefore, ghrelin quickens people's stomach emptying (Peeters, T.L.Curr.Opin.Pharmacol.2006,6,553-558; Tack, J.; Depoortere, I.; Bisschops, R.; Delporte, C.; Coulie, B.; Meulemans, A.; Janssens, J.; Peeters, T.Gut 2006,55,327-333; Inui, A.; Asakawa, A.; Bowers, C.Y.; Mantovani, G.; Laviano, A.; Meguid, M.M.; Fujimiya, M.FASEB J.2004,18,439-456; Peeters, T.L.J.Physiol.Pharmacol.2003,54 (supplementary issues 4), 95-103.), and it has proved the beneficial agents of treatment POI in animal model.(Trudel，L.；Tomasetto，C.；Rio，M.C.；Bouin，M.；Plourde，V.；Eberling，P.；Poitras，P.Am.J.Physiol.2002，282，G948-G952；Trudel，L.；Bouin，M.；Tomasetto，C.；Eberling，P.；St-Pierre，S.；Bannon，P.；L’Heureux，M.C.；Poitras，P.Peptides?2003，24，531-534；De?Winter，B.Y.；De?Man，J.G.；Seerden，T.C.；Depoortere，I.；Herman，A.G.；Peeters，T.L.；Pelckmans，P.A.Neurogastroenterol.Motil.2004，16，439-446。) the ghrelin agonist doubles the effect of ghrelin, therefore directly the basic cause of disease of target POI and can be left hospital faster promoting the normalizing of intestinal function.(Kitazawa，T.；De?Smet，B.；Verbeke，K.；Depoortere，I.；Peeters，T.L.Gut?2005，54，1078-1084；Poitras，P.；Polvino，W.J.；Rocheleau，B.Peptides?2005，26，1598-1601。) anti-inflammatory action of the ghrelin reported also can work in improving this illness.(Granado，M.；Priego，T.；Martin，A.I.；Villanua，M.A.；Lopez-Calderon，A.Am.J.Physiol.Endocrinol.Metab.2005，288，E486-E492；Iseri，S.O.；Sener，G.；Yuksel，M.；Contuk，G.；Cetinel，S.；Gedik，N.；Yegen，B.C.J.Endocrinol.2005，187，399-406。)
It often is the optimization approach of treatment POI that intravenously is used, and this is because these patients' injured GI motion has hindered oral administration.There is not drugs approved by FDA to be specifically designed to the medicament of treatment POI at present.
Another main motion illness is a gastroparesis, the peculiar problem of I type and type ii diabetes.(Camilleri, M.Advances in diabetic gastroparesis (progress of diabetic gastroparesis).Rev.Gastroenterol.Disord.2002，2，47-56；Abell，T.L.；Bernstein，R.K.；Cutts，T.Neurogastrenterol.Motil.2006，18，263-283；Camilleri，M.New?Eng.J.Med.2007，356，820-829。) gastroparesis (" stomach paralysis ") is being the syndrome of feature without any the stomach emptying that postpones under the mechanical obstruction.It is characterized by stomachache erratically, feel sick, vomiting, weight saving, apocleisis, early full (early satiety), malnutrition, dehydration, gastroesophageal reflux, spasm and swelling.This chronic disease can cause frequent hospital care, the increase of deformity and the decline of quality of life.(Wang，Y.R.；Fisher，R.S.；Parkman，H.P.Am.J.Gastro.2007，102，1-10。) serious, symptomatic gastroparesis (symptomatic gastroparesis) is common in suffering from the individuality of diabetes, only in the U.S., in 100 ten thousand diabetic subject's total populations, just has 5-10% influenced by it.Neuropathy is that diabetes common makes us weak complication.The splanchnic nerve disease causes GI dysfunction (being particularly related to stomach), and causes injured stomach motion.Ghrelin promotes stomach emptying by vagus nerve stimulation and via the direct kinetogenesis to gastric mucosa.In addition, up-to-date clinical study shows that intravenously is used natural auxin release peptide acute treatment diabetic gastroparesis patient (Binn, M. effectively; Albert, C.; Gougeon, A.; Maerki, H.; Coulie, B.; Lemoyne, M.; Rabasa Lhoret, R.; Tomasetto, C.; Poitras, P.Peptides 2006,27,1603-1606; Murray, C.D.R.; Martin, N.M.; Patterson, M.; Taylor, S.; Ghatei, M.A.; Kamm, M.A.; Johnston, C.; Bloom, S.R.; Emmanuel, A.V.Gut 2005,54,1693-1698; Tack, J.; Depoortere, I.; Bisschops, R.; Verbeke, K.; Janssens, J.; Peeters, T.Aliment.Pharmacol.Ther.2005,22,847-853.)
Therefore, the ghrelin agonist will very overcome the basic dyskinesia that the gastroparesis patient is faced effectively, and revise this illness.The same with POI, do not obtain generally acknowledge or effective treatment, and most of current treatment is intended to only provide remission to diabetic gastroparesis.In addition, the treatment in many exploitations has the mechanism of action similar to the early production of having failed in this indication.Operation technique can be alleviated lysis, but does not provide the possibility of healing.
The postoperative gastroparesis syndrome is the complication that causes of operation, it is characterized by the stomach emptying of delay, nausea and vomiting and stomachache after the meal.(Eckhauser, people Am.Surg.1998 such as F.E., 64,711-717; Tanaka, M.Surg.Today 2005,35,345-350.) these operations are included in gastrectomy, pancreatoduodenectomy, the gastrojejunostomy in carcinoma of the pancreas and stomach operation patient and the liver cirrhosis patient.(Doberneck，R.C.；Berndt，G.A.Arch.Surg.1987，122，827-829；Bar-Natan，M.；Larson，G.M.；Stephens，G.；Massey，T.Am.J.Surg.1996，172，24-28；Cohen，A.M.；Ottinger，L.W.Ann.Surg.1976，184，689-696；Isobe，H.；Sakai，H.；Satoh，M.；Sakamoto，S.；Nawata，H.Dig.Dis.Sci.1994，39，983-987。) show to the useful unique report medicament of this syndrome it is cisapride and erythromycin.(Takeda，T.；Yoshida，J.；Tanaka，M.；Matsunaga，H.；Yamaguchi，K.；Chijiiwa，K.Ann.Surg.1999，229，223-229；Heidenreich，A.；Wille，S.；Hofmann，R.J.Urology?2000，163，545。Yet), cisapride descends the city, this to small part be because the appearance of life-threatening arrhythmia (cardiac arythmia) side effect.In addition, erythromycin is not the ideal treatment, and this is that it should be used for non-infection purpose owing to the tolerific anti-microbial activity of possibility.
Term OPIOIDS inductive intestinal dysfunction (OBD, Kurz, A.; Sessler, D.J.Drugs2003,63,649-671.) be used to comprise the compiling of symptom of the GI hypokinesis that causes by the treatment of OPIOIDS analgesic agent.Take about 40-50% that OPIOIDS is used for the patient of pain control and stand OBD.It is characterized by do something in disregard of obstacles just, the gastric reflux of trouble urinating (straining), not exclusively drainage, swelling, abdominal distension and increase.Except tangible short-term misery, this illness produces health and menticide in the patient who stands long-term OPIOIDS treatment.In addition, dysfunction may so seriously consequently become the dose limitation side effect, and in fact it stoped enough pain control.The same with POI, can expect that the ghrelin agonist is offset by OPIOIDS to use the dyskinesia that produces.
GI motion stimulatory effect by ghrelin and ghrelin agonist also can help two kinds of uncommon syndromes.Short bowel syndrome is the illness that occurs after the surgical blanking of substantial part (substantial portion) of small intestine, and is feature with the malnutrition.Observe the ghrelin level that the patient has the reduction that the loss by the neuroendocrine cell of the generation ghrelin of intestines causes.Short intestines are possible to the feedback that hormone discharges.(Krsek, M.; Rosicka, M.; Haluzik, people Endocr.Res.2002 such as M., 28,27-33.) chronic intestinal pseudo-obstruction is by existing chronic intestines to expand and the defined syndrome of dyskinesia under mechanical obstruction or the inflammation lacking.The genetic cause and the acquired character reason that produce this illness are known, and described illness worldwide influences many individualities every year.(Hirano，I.；Pandolfino，J.Dig.Dis.2000，18，83-92。)
Other illness that can handle by the plain releasing peptide receptor of stimulating growth with illness are: such as stomach emptying, gastroesophageal reflux disease (GERD), stomach ulcer (Sibilia, the V. of the constipation relevant with the hypomotility stage of irritable bowel syndrome (IBS), the relevant delay with the expendable illness; Muccioli, G.; Deghenghi, R.; Pagani, F.; DeLuca, V.; Rapetti, D.; Locatelli, V.; Netti, C.J.Neuroendocrinol.2006,18,122-128; Sibilia, V.; Rindi, G.; Pagani, F.; Rapetti, D.; Locatelli, V.; Torsello, A.; Campanini, N.; Degenghi, R.; Netti, C.Endocrinology 2003,144,353-359.) and crohn.Ghrelin and ghrelin agonist also are described to treatment and feel sick, vomit or its symptom.(No. the 2005/277677th, U.S. Patent Application Publication; Rudd, J.A.; Ngan, M.P.; Wai, M.K.; King, A.G.; Witherington, J.; Andrews, P.L.R.; Sanger, G.J.Neurosci.Lett.2006,392,79-83.)
In addition, the GI dyskinesia also is major issue in other Mammalss.For example, the dyskinesia that is called intestinal obstruction or angina is first reason of horse death.In addition, intestinal obstruction is one of the most common complication of the intestinal surgery of horse, is also referred to as postoperative ileus.This illness may also have the nonoperative cause of disease.According to them gastral anatomy and function, some Markos can easily suffer from intestinal obstruction.In fact, any horse all easily suffers from angina, according to age, sex and kind small difference is only arranged.In addition, intestinal obstruction may influence other animal, for example dog.(Roussel，A.J.，Jr.；Cohen，N.D.；Hooper，R.N.；Rakestraw，P.C.J.Am?Vet.Med.Assoc.2001，219，72-78；VanHoogmoed，L.M.；Nieto，J.E.；Snyder，J.R.；Harmon，F.A.Vet.Surg.2004，33，279-285。)
Drug-induced untoward reaction is the known complication of all types of pharmacotherapys.Gastrointestinal side-effect is to use one of most common complication that medicine stands, and occurs in the 20%-40% of all cases.(Lewis，J.H.Am.J.Gastroenterol.1986，81，819-834；Henry，D.A.；Ostapowicz，G.；Robertson，J.Clin.Gastroenterol.1994，8，271-300。) more seriously, in inpatient, estimate that 25% drug-induced reaction relates to gi tract, in the small proportion case, have fatal possibly result.(Stewart，R.B.；Cluff，L.E.Am.J.Dig.Dis.1974，19，1-7。) side effect can influence GI all parts.(Gore，R.M.；Levine，M.S.；Ghahremani，G.G.Abdom.Imaging?1999，24，9-16；Neitlich，J.D.；Burrell，M.I.Abdom.Imaging?1999，24，17-22；Neitlich，J.D.；Burrell，M.I.Abdom.Imaging?1999，24，23-38。) this side effect only can be handled by reducing dosage usually, so the frequent effectiveness that reduces medicine.In addition, owing to stand these side effects, the patient cuts out their medicine frequently simply.
The GI side effect is common in many definite drug types, described drug type comprises anticholinergic (coromegine for example, Benzatropine (benzotropine), Scopolamine, Propanthelinium, scopolamine, Trihexyphenidyl), tricyclics (thiodiphenylamine for example, amitriptyline, Sensaval), monoamine uptake blocker thymoleptic (Desipramine for example, fluoxetine, citalopram, nomifensine), other psychotropic, cancer chemotherapeutic agent (for example vincristine(VCR)), be used for hypertensive 2-adrenergic agonist components, particularly beta-2-agonists and α 2-agonist (for example Racemic isoproterenol, salbutamol, lidamidine, clonidine), dopaminergic (for example levodopa, bromocriptine, apomorphine), antimalarial drug (for example chloroquine, Quinacrine), spasmolytic (for example pavatrine (pavatrine)) and many other medicaments (for example zonisamide, pergolide, Ibudilast, mexiletine, acarbose, Sodium Valproate, hexamethylamine, alendronate).
In addition, many newer medicines although be hopeful to improve a series of treatment of diseases, also stand the GI side effect.The agonist of glucagon-like peptide 1 (GLP-1), dextrin and peptide YY (PYY) acceptor belongs to this class medicine, and they are very useful to treatment diabetes and/or other metabolic disorder.The LTRA that the other drug type that shows the GI side effect is the proteasome inhibitor (a kind of new chemotherapeutic is often as assisting therapy) that is used for cancer, be used for asthma and other inflammatory diseasess (pranlukast for example, Garcia, M.; Nakabayashi, T.; Mochiki, E.; Naga, N.; Pacheco, I.; Suzuki, T.; Kuwano, H.Dig.Dis.Sci.2004,49,1228-1235), phosphodiesterase-5 (PDE-5) inhibitor (Virga: Dishy for example, V.; Pour, M.C.; Feldman, L.Clin.Pharm.Ther.2004,76,281-286) and modulators of nicotinic acetylcholine receptors (Mandl, P.; Kiss, J.P.Brain Res.Bull.2007,72,194-200).
Many novel drugs treatments that are used for metabolic disorder have been used or are just under development.Unfortunately, many in these pharmacological agenies show stomach and intestine (GI) side effect, and it can cause, and effect reduces, relatively poor patient's conformability and even make patient's drug withdrawal.
For example, the GLP-1 agonist such as Exenatide (exenatide) belongs to the most effective new medicament that is used for the treatment of diabetes.Yet this mechanism of action also causes the remarkable reduction of stomach emptying.(Nauck，M.A.；Niedereichholz，U.；Ettler，R.；Holst，J.J.；Orskov，C.；Ritzel，R.；Schmiegel，W.H.Am.J.Physiol.1997，273，E981-E988；Tolessa，T.；Gutniak，M.；Holst，J.J.；Efendic，S.；
Figure G2008800105877D00171
P.M.J.Clin.Invest.1998，102，764-774；Little，T.J.；Pilichiewicz，A.N.；Russo，A.；Phillips，L.；Jones，K.L.；Nauck，M.A.；Wishart，J.；Horowitz，M.；Feinle-Bisset，C.J.Clin.Endocrmol.Metab.2006，91，1916-1923；Bamett，A.Exp.Opin.Pharmacother.2007，8，2593-2608。) because the stomach emptying that postpones, or gastroparesis has been diabetic subject's known problem, and this side effect has increased the weight of very situation of difficult.
Similarly, tripro-amylin is introduced as the dextrin agonist, it also is used for the treatment of diabetes.Unfortunately, the essence of its mechanism of action reduces stomach emptying.(Young，A.Adv.Pharmacol.2005，52，99-121。)
Peptide YY agonist similarly has the potential use of treatment metabolic disorder, but also reduces stomach emptying.(Chelikani，P.K.；Haver，A.C.；Reidelberger，R.D：Am.J.Physiol.2004，287，R1064-R1070。)
Similarly, with proteasome inhibitor as useful treatment, introduce separately or with other chemotherapeutics combinations, be used for the treatment of many hyper-proliferative illnesss, comprise many dissimilar cancers.Yet one of these medicines--Velcade (bortezomib) also causes the stomach and intestine transportation of delay.(Perfetti，V.；Palladini，G.；Brunetti，L.；Sgarella，A.；Brugnatelli，S.；Gobbi?P.G.；Corazza，G.R.Eur.J.Gastroenterol.Hepatol.2007，19，599-601。)
The ghrelin agonist (as growth hormone cinogenic agent, GHS), be not the present invention describe those, use, although do not offset drug-induced GI side effect clearly with multiple combination with other therapeutic agents.Reported that GHS and selective estrogen receptor modulators (SERM) combination is used for the treatment of flesh bone fragility (muscoskeletal frailty) (WO 99/65486, WO99/65488, GB 2324726).EP 1149583 has discussed that GHS is used for the treatment of osteoporosis with corticotropin releasing factor (CRF) antagonist as medicine and such as the cardiovascular disorder of congestive heart failure.Describe GHS and thymoleptic and made up the quality (WO01/089570) that is used to make the life better.
Many combinations of medicament and GHS have come into question and have been used for the treatment of alzheimer's disease, comprise with inhibitors of phosphodiesterase-4 (WO 2004/087157), make up with β-amylaceous properties-correcting agent (WO2004/110443) and p38 kinase inhibitor (WO 2005/058308).US 6,657, and 063 has reported GHS and β 3-adrenergic agonist group is share in the treatment type ii diabetes.GHS has been used for emaciation, appetite reduction and increase ingestion of food with the GH combination, and (WO 2005/097173; WO2005/097174).WO 2006/092106 has described a kind of representational GHS, and GHRP-6 and Urogastron (EGF) are used for autoimmunization and CNS disease.
The combination of having described other medicaments is used for multiple GI illness.These comprise acetylcholinesterase depressant with anticholinergic as being used for the treatment (US2004/082644) of chronic intestinal pseudo-obstruction.WO 2006/005613 discloses inhibitors of dipeptidyl IV and 5-HT 3And 5-HT 4The conditioning agent combination is used for the GI illness.
Specifically the report at the drug regimen of GI motion illness is known, comprises 5-HT 3It is the disease (WO 2007/005780) of feature that agonist and second kind of compound are treated together with the hypomotility.5-HT 3Antagonist and 5-HT 4Agonist and second kind of medicament are described in WO 01/041748 and US2004/092511.
Reported proton pump inhibitor (PPI) and activator combination (WO 2005/065664) and with the combination (WO 2004/105795) of GI motion medicament.PPI and the method for the compound combination that improves gastrointestinal motility have also been reported as treatment gastroesophageal reflux disease (GERD, No. the 2006/0241134th, U.S. Patent Application Publication).Activator promise cisapride (norcisapride) with PPI and H 2-antagonist (such as Berberine) is used in combination that (WO 00/051583; WO 00/051584).
Yet, still need other combination, such as pharmaceutical composition of the present invention, it can handle the drug-induced GI side effect from some drugs such as previous general introduction.
Importantly be for the great majority of above illness, do not have the therapy of specific approved, and most of therapy only to be engaged in the alleviation of symptom.Yet the site that the particular adjustments of ghrelin receptor provides the disorder of direct target pathologic, physiologic is to treat potential illness better and to improve the chance of clinical effectiveness.In addition, in animal model, shown that the Macrocyclic ghrelin agonist does not stimulate the GH secretion simultaneously.(Venkova，K.；Fraser，G.；Hoveyda，H.R.；Greenwood-Van?Meerveld，B.Dig.Dis.Sci.2007，52，2241-2248。) the former this stomach and intestine of any conditioning agent and separating of GH effect of not reporting ghrelin receptor.Yet, as already mentioned, reported recently to have analogue that it has separated appetite control and the GH relevant with ghrelin and has regulated effect (Halem, H.A.; Taylor, J.E.; Dong, people Eur.J.Endocrinol.2004 such as J.Z., 151, S71-S75).
WO 01/00830 has discussed secretion tethelin and has promoted that (short gastrointestinal peptides SGIP), but does not show that these are because act on ghrelin receptor to the short gastrointestinal peptide of GI motion.Similarly, WO 2007/041278 has described the peptide analogs of the ghrelin that stimulates the GI motion.United States Patent (USP) the 6th, 548,501 and 6,852, the concrete non-peptide GHS compound that is used to stimulate the GI motion has been discussed for No. 722.Similarly, WO 2006/010629, WO2006/020930 and WO 2006/023608 have described the ghrelin agonist (growth hormone cinogenic agent) that is used for the GI illness.In addition, known other castle's intrinsic factor stimulates the secretion of GH, but does not promote the GI motion.In fact, in fact many castle's intrinsic factors suppress this physiological function.Such as the concrete receptor stimulant of compound of the present invention, having bigger potentiality becomes selectivity and effective therapeutical agent.
International Patent Application WO 2006/009645 and WO 2006/009674 have described macrocylc compound as the purposes of ghrelin conditioning agent in being used for the treatment of the G1 illness.In the POI rat model, reported a kind of activity in these compounds.(Venkova，K.；Fraser，G.；Hoveyda，H.R.；Greenwood-Van?Meerveld，B.Dig.Dis.Sci.2007，52，2241-2248。) these macrocylc compound structurally are different with what found as agonist and interactional other compounds of ghrelin receptor.For example, main work be devoted to the exploitation of a large amount of small molecules derivatives powerful and GHS optionally, described small molecules derivative is known as nearest summary at present.(Carpino，P.Exp.Opin.Ther.Patents?2002，12，1599-1618。) concrete GHS describes in following patent: international application published WO89/07110; WO 89/07111; WO 92/07578; WO 93/04081; WO 94/11012; WO 94/13696; WO 94/19367; WO 95/11029; WO 95/13069; WO95/14666; WO 95/17422; WO 95/17423; WO 95/34311; WO 96/02530; WO 96/15148; WO 96/22996; WO 96/22997; WO 96/24580; WO96/24587; WO 96/32943; WO 96/33189; WO 96/35713; WO 96/38471; WO 97/00894; WO 97/06803; WO 97/07117; WO 97/09060; WO97/11697; WO 97/15191; WO 97/15573; WO 97/21730; WO 97/22004; WO 97/22367; WO 97/22620; WO 97/23508; WO 97/24369; WO97/34604; WO 97/36873; WO 97/38709; WO 97/40023; WO 97/40071; WO 97/41878; WO 97/41879; WO 97/43278; WO 97/44042; WO97/46252; WO 98/03473; WO 98/10653; WO 98/18815; WO 98/22124; WO 98/46569; WO 98/51687; WO 98/58947; WO 98/58948; WO98/58949; WO 98/58950; WO 99/08697; WO 99/08699; WO 99/09991; WO 99/36431; WO 99/39730; WO 99/45029; WO 99/58501; WO99/64456; WO 99/65486, and WO 99/65488; WO 00/01726; WO 00/10975; WO 00/48623; WO 00/54729; WO 01/47558; WO 01/92292; WO01/96300; WO 01/97831; WO 2004/021984; WO 2005/039625; WO2005/046682; WO 2005/070884; WO 2006/044359; United States Patent (USP) the 3rd, 239, No. 345; United States Patent (USP) the 4th, 036, No. 979; United States Patent (USP) the 4th, 411, No. 890; United States Patent (USP) the 5th, 492, No. 916; United States Patent (USP) the 5th, 494, No. 919; United States Patent (USP) the 5th, 559, No. 128; United States Patent (USP) the 5th, 663, No. 171; United States Patent (USP) the 5th, 721, No. 250; United States Patent (USP) the 5th, 721, No. 251; United States Patent (USP) the 5th, 723, No. 616; United States Patent (USP) the 5th, 726, No. 319; United States Patent (USP) the 5th, 767, No. 124; United States Patent (USP) the 5th, 798, No. 337; United States Patent (USP) the 5th, 830, No. 433; United States Patent (USP) the 5th, 919, No. 777; United States Patent (USP) the 6th, 034, No. 216; United States Patent (USP) the 6th, 548, No. 501; United States Patent (USP) the 6th, 559, No. 150; United States Patent (USP) the 6th, 576, No. 686; United States Patent (USP) the 6th, 639, No. 076; United States Patent (USP) the 6th, 686, No. 359; United States Patent (USP) the 6th, 828, No. 331; United States Patent (USP) the 6th, 861, No. 409; United States Patent (USP) the 6th, 919, No. 315; United States Patent (USP) the 7th, 034, No. 050 and Application No. 2002/0168343; 2003/100494; 2003/130284; 2003/186844; 2005/187237; 2005/233981.
However a large amount of work finds that seldom cyclic cpds acts on ghrelin receptor.When they were found, antagonistic activity was more preponderated.For example, proved 14-amino-acid compound vapreotide, a kind of SRIH-14 agonist and somatostatin stand-in are ghrelin antagonists.(Ghigo E waits human endocrine 2001,14,29-33 for Deghenghi R, Papotti M.) reported combination and the antagonistic activity (International Patent Application WO 03/004518) of the analogue (a kind of known ring-type neuropeptide that non-selectively is incorporated into the somatostatin receptor) of hydrocortisone stabilize proteins (cortistatin) to secretagogue receptor.(Deghenghi R, Broglio F, people Endocrine 2003,22 such as Papotti M, 13-18; Sibilia, V.; Muccioli, G.; Deghenghi, R.; Pagani, F.; DeLuca, V.; Rapetti, D.; Locatelli, V.; Netti, C.J.Neuroendocrinol.2006,18,122-128.) especially, one of these analogues, EP-01492 (hydrocortisone stabilize proteins-8) has entered the preclinical study of treatment of obesity as the ghrelin antagonist, though nearest research model is queried its effectiveness.(Prodam, F.; Benso, A.; Gramaglia, E. neuropeptide 2008,42,89-93.) these compounds show the IC of 24-33nM 50In addition, described the derivative of these ring compounds and they, added that they use the radiodiagnosis or the radiotherapy that can be used in tumour and acromegaly treatment to use with metallic bond.
Studied the treatment (WO99/12969) of the ring-type of tethelin 177-191 and linear analogue, and a kind of special compd A OD9604 has entered clinical this indication that is used for as obesity.The compound the most similar to molecule of the present invention after deliberation is GHS, G-7203 (EC 50=0.43nM), the cyclic peptide analogue of growth hormone-releasing peptide GHRP-2.(Elias，K.A.；Ingle，G.S.；Burnier，J.P.；Hammonds，G.；McDowell，R.S.；Rawson，T.E.；Somers，T.C.；Stanley，M.S.；Cronin，M.J.Endocrinol.1995，136，5694-5699。Yet), the simplification of this cyclic derivatives still produces powerful ol cpds, and for compound of the present invention, has found that linear analogue does not have the ghrelin receptor activity.
Shown that macrocylc compound of the present invention has ghrelin and regulates activity, and in special embodiment, it is an agonist.The conditioning agent of Macrocyclic peptides stand-in (peptidomimetics) as ghrelin receptor before described, and they (international application published WO 2006/009645 in the treatment GI of multiple conclusion and the purposes in the metabolic disorder; 2006/009674; WO2006/046977; 2006/137974 U.S. Patent Application Publication No. 2006/025566; 2007/0021331; Application No. 11/774,185).One of these compounds have entered clinical.(Lasseter, K.C.; Shaughnessy, L.; Cummings, people J.Clin.Pharmacol.2008 such as D., 48,193-202).
Although binding ability and target avidity are the factors of drug discovery and exploitation, to the exploitation of feasible medicament also importantly pharmacokinetics (PK) and pharmacodynamics (PD) Parameter Optimization.In the pharmaceutical industry, the focus area of research is a latency of understanding decision molecule suitability by this way better, generically is called " quasi-medicated property " usually.(Lipinski，C.A.；Lombardo，F.；Dominy，B.W.；Feeney，P.J.Adv.Drug?Delivery?Rev.1997，23，3-25；Muegge，I.Med.Res.Rev.2003，23，302-321；Veber，D.F.；Johnson，S.R.；Cheng，H.-Y.；Smith，B.R.；Ward，K.W.；Kopple，K.D.J.Med.Chem.2002，45，2615-2623。) for example, all the compound with successful in drug development is relevant for the quantity of the quantity of molecular weight, log P, membrane permeability, hydrogen-bond donor and acceptor, total polar surfaces long-pending (TPSA) and rotatable key.In addition, in pharmaceutical industry, plasma proteins in conjunction with, be used to select and develop new drug candidates with the interaction of cytochrome P 450 enzymes and the experiment measuring of pharmacokinetic parameter.
Yet in the macrocyclic structure type, these parameters are not widely studied or report.The shortage of this information produces challenge in the drug development of this quasi-molecule.Found that macrocylc compound of the present invention has the pharmacological characteristic of expectation, kept simultaneously ghrelin receptor enough binding affinity and selectivity, illustrated as embodiment provided herein.These combined feature make compound of the present invention be more suitable for being developed to medicament than the big ring of before having reported usually, are particularly suitable for as Orally administered medicament or life-time service.
Summary of the invention
The invention provides the macrocylc compound that novel conformation is determined.These compounds can play the effect of the conditioning agent, particularly agonist of ghrelin (growth hormone cinogenic agent) acceptor (GHS-R1a).
According to each side of the present invention, the present invention relates to compound and pharmacy acceptable salt thereof according to formula I
Wherein:
R 1Be selected from the group of forming by the low alkyl group of cycloalkyl, low alkyl group and the replacement of cycloalkyl, replacement;
R 2Be selected from the group of forming by the low alkyl group of low alkyl group and replacement;
R 3Be selected from by alkyl, with the alkyl of hydroxyl or carboxyl substituted and the group formed with the alkyl that aryl replaces;
R 4, R 5a, R 5b, R 6And R 7Be independently selected from the group of forming by hydrogen and low alkyl group;
R 8aAnd R 8bBe independently selected from the group of forming by hydrogen and low alkyl group;
Y is CR 9aR 9bR wherein 9aAnd R 9bBe independently selected from the group of forming by hydrogen and low alkyl group;
Z is selected from:
Figure G2008800105877D00232
Wherein (A) and (Y) represent that respectively Z arrives the CR of formula I 5aR 5bKey with Y;
L 1, L 2And L 3Be independently selected from by O and CR 10aR 10bThe group of forming; R wherein 10aAnd R 10bBe independently selected from the group of forming by hydrogen and low alkyl group;
M 1, M 2, M 3And M 4Be independently selected from the group of being made up of C and N, condition is maximum M 1, M 2, M 3And M 4In one be nitrogen;
X 1, X 2, X 3, X 4, X 5, X 6And X 7Be independently selected from the group of forming by hydrogen, halogen, trifluoromethyl, hydroxyl, alkoxyl group and low alkyl group;
M is 0 or 1; And n is 1 or 2.
Each side of the present invention also provides the compound of formula II, or its optical isomer, enantiomorph or diastereomer:
Wherein:
R 18, R 19a, R 19b, R 20And R 21Be independently selected from the group of forming by the low alkyl group of hydrogen, low alkyl group and replacement;
R 22Be selected from the group of forming by the standard protecting group of hydrogen, alkyl, acyl group, alkylsulfonyl and hydroxy functional group;
R 23Be selected from the group of forming by the standard protecting group of hydrogen, alkyl, acyl group, carboxyalkyl, carboxyl aryl, alkylsulfonyl and amine functional group;
R 24Be selected from the group of forming by hydrogen and alkyl;
B is CR 25aR 25bR wherein 25aAnd R 25bBe independently selected from the group of forming by hydrogen and low alkyl group;
W is selected from the group of being made up of following:
Wherein (D) and (B) represent that respectively W arrives the CR of formula II 19aR 19bKey with B;
L 4, L 5And L 6Be independently selected from by O and CR 26aR 26bThe group of forming; R wherein 26aAnd R 26bBe independently selected from the group of forming by hydrogen and low alkyl group;
M 5, M 6, M 7And M 8Be independently selected from the group of being made up of C and N, condition is maximum M 5, M 6, M 7And M 8In one be nitrogen;
X 8, X 9, X 10, X 11, X 12, X 13And X 14Be independently selected from the group of forming by hydrogen, halogen, trifluoromethyl, hydroxyl, alkoxyl group and low alkyl group;
P is 0 or 1; And q is 1 or 2.
Further aspect of the present invention provides and comprises (a) element structure (building block structure); (b) macrocylc compound of the compound of formula II, or derivatives thereof, and the method for the compound of the compounds accepted way of doing sth I of the formula of use II.
Each side of the present invention further provides pharmaceutical composition, and it comprises the compound of formula I or formula II and pharmaceutically acceptable carrier, vehicle or thinner.In some embodiments, this pharmaceutical composition comprises the ghrelin receptor agonist, and at least a in GLP-1 receptor stimulant, dextrin receptor stimulant, peptide YY (PYY) receptor stimulant and the proteasome inhibitor, together with pharmaceutically acceptable carrier, vehicle or thinner.
Each side of the present invention provides the method for treatment gastrointestinal disorder, metabolism or endocrine disorder, cardiovascular disorder, central nervous system disorders, inflammatory conditions, osteopathy or hyper-proliferative illness, comprises compound from the formula I of significant quantity to its curee of needs that use.
Additional aspects of the present invention provide test kit, and it comprises one or more containers and packs with optional its working instructions, and described container comprises pharmaceutical dosage unit, and this pharmaceutical dosage unit contains one or more compounds of the present invention of significant quantity.
Each side of the present invention further provides the stimulating gastrointestinal motion, regulates the method for mammiferous GHS-R1a receptor active and/or treatment gastrointestinal disorder, it comprises conditioning agent from significant quantity to its curee of needs that use, and this conditioning agent is regulated mammiferous GHS-R1a acceptor.In other embodiments, this conditioning agent is the compound of formula I.
Additional aspects of the present invention provide the method for diagnosis and treatment tumour and/or acromegaly, diagnostic method comprises uses compound of the present invention and radiolabeled metallic bond, and detecting combining of said composition and biological target, methods of treatment comprises the composition that comprises The compounds of this invention of administering therapeutic significant quantity.
Other aspects of the present invention provide uses compound of the present invention, and all suc as formula I those suffer from curee reduction or handicapped gastrointestinal motility who is caused by particular agent (such as medicine, medicine or pharmaceutical composition) with treatment.In some embodiments, this particular agent has been used for the treatment of curee's metabolism, hyper-proliferative or other illnesss.In addition, compound of the present invention can be used for preventing and treating reduction or the handicapped gastrointestinal motility that can be caused by particular agent.
Further aspect of the present invention relates to the method for the compound of preparation formula I or formula II.
Each side of the present invention further relates to the method that prevents and/or treats illness described herein, described illness is gastrointestinal disorder particularly, comprise postoperative ileus, gastroparesis (such as diabetic and postoperative gastric paresis), OPIOIDS inductive intestinal dysfunction, chronic intestinal pseudo-obstruction, short bowel syndrome, such as the vomiting that causes by cancer chemotherapeutic, such as with the relevant constipation of hypomotility stage of irritable bowel syndrome (IBS), the stomach emptying of the delay relevant with the expendable illness, gastroesophageal reflux disease (GERD), stomach ulcer, crohn, with the dyskinesia is gastrointestinal disorder and the GI other diseases and the illness of feature.
In specific embodiment, gastrointestinal disorder is a postoperative ileus, gastroparesis, OPIOIDS inductive intestinal dysfunction, chronic intestinal pseudo-obstruction, acute colon Pseudo-Obstruction (Ogilvie syndrome), short bowel syndrome, vomiting, constipation is main irritable bowel syndrome (IBS), chronic constipation, the maldigestion syndrome that cancer is relevant, the stomach emptying that postpones, the gastrointestinal dysfunction among the Parkinson's disease patient or the stomach emptying of delay, the gastrointestinal dysfunction in the steirert-Batten-Gibb syndrome or the stomach emptying of delay, the gastrointestinal dysfunction among scleroderma (scerloderma) patient or the stomach emptying of delay, gastroesophageal reflux disease (GERD), stomach ulcer or crohn.
The invention still further relates to the formula I that is used to prepare the medicine that is used for preventing and/or treating illness described herein and/or the compound of formula II.
Explain in further detail in the specification sheets that above-mentioned and other aspects of the present invention are stated below.
The accompanying drawing summary
Fig. 1 represents the concentration-response figure with the signal transduction path of exemplary compounds activation ghrelin receptor of the present invention mediation.
Fig. 2 represents to describe the figure of the influence that exemplary compounds paired pulses formula tethelin of the present invention discharges.
Fig. 3 represents description specifically behind the Orally administered 8mg/kg compound 802 (figure A) and behind the Orally administered 8mg/kg compound 807 (figure B), the figure of the pharmacokinetic parameter of exemplary compounds of the present invention.
Fig. 4 represents description specifically behind the Orally administered 8mg/kg compound 810 (figure A) and behind the Orally administered 8mg/kg compound 819 (figure B), the figure of the pharmacokinetic parameter of exemplary compounds of the present invention.
Fig. 5 represents description specifically behind the Orally administered 2mg/kg compound 822 (figure A) and behind the Orally administered 8mg/kg compound 825 (figure B), the figure of the pharmacokinetic parameter of exemplary compounds of the present invention.
Fig. 6 represents description specifically behind the Orally administered 8mg/kg compound 831 (figure A) and behind the Orally administered 8mg/kg compound 854 (figure B), the figure of the pharmacokinetic parameter of exemplary compounds of the present invention.
Fig. 7 represents description specifically behind the Orally administered 8mg/kg compound 877 (figure A) and behind the Orally administered 8mg/kg compound 968 (figure B), the figure of the pharmacokinetic parameter of exemplary compounds of the present invention.
Fig. 8 represents description specifically behind the Orally administered 8mg/kg compound 1011 (figure A) and behind the Orally administered 8mg/kg compound 1069 (figure B), the figure of the pharmacokinetic parameter of exemplary compounds of the present invention.
Describe in detail
Now according to other embodiments as herein described above and other of the present invention aspect is described in further detail. Should be understood that the present invention can specialize with different forms, and should not be interpreted as limiting the embodiment that this paper states. On the contrary, provide these embodiments, so that present disclosure will be detailed and completely, and scope just of the present invention intactly is conveyed to those skilled in the art.
Used term is only in order to describe the purpose of specific embodiment in the specification of the present invention, and is not intended to limit the present invention. As used in specification of the present invention and appended claim, singulative " (a) ", " one (an) " and " should (the) " also mean to comprise plural form, unless point out in addition clearly in the context. As used herein in addition, term " and/or " comprise the one or more any He all combinations in the relevant listed term, and can be abbreviated as "/".
Unless otherwise defined, under all technology used herein and scientific terminology and the present invention any those of ordinary skill institute in field the implication of understanding is identical usually.
Other lists of references that all publications, U.S. Patent application, United States Patent (USP) and this paper quote by reference integral body are incorporated into.
Term " alkyl " refers to the undersaturated alkyl of saturated or part of straight or branched, and it has from 1 to 20 carbon atom, is 1 to 8 carbon atom in some instances. Term " low alkyl group " refers to contain the alkyl of 1 to 6 carbon atom. The example of alkyl includes but not limited to methyl, ethyl, isopropyl, the tert-butyl group, 3-hexenyl and 2-butynyl. " unsaturated " refers to exist 1,2 or 3 two key or triple bond or both combinations. As mentioned below, this class alkyl also can randomly be replaced.
When using lower timestamp about alkyl defined herein or other alkyl, this subscript refers to the quantity of the carbon atom that group can contain. For example, C2-C 4Alkyl refers to have the alkyl of 2,3 or 4 carbon atoms.
Term " cycloalkyl " refers to saturated or the undersaturated cyclic hydrocarbon radical of part, and it has from 3 to 15 carbon atoms in the ring, is 3 to 7 carbon atoms in some instances, also refers to contain the alkyl of described cyclic hydrocarbon radical. The example of cycloalkyl includes but not limited to cyclopropyl, cyclopropyl methyl, cyclopenta, 2-(cyclohexyl) ethyl, suberyl and cyclohexenyl group. Cycloalkyl also comprises the group with a plurality of carbocyclic rings as herein defined, and each carbocyclic ring can be saturated or part is undersaturated, for example decahydro naphthyl, [2.2.1]-bicycloheptane base or adamantyl. As mentioned below, all these cycloalkyl also can randomly be replaced.
Term " aromatic compound " refers to have the undersaturated cyclic hydrocarbon radical of the conjugated pi electron system that contains 4n+2 electronics, and wherein n is the integer more than or equal to 1. Aromatic molecule is normally stable, and is described to have the planar rings of the atom of the resonant structure that is comprised of the two keys that replace and singly-bound, for example benzene or naphthalene.
Term " aryl " refers to aromatic radical single or the fused iso system, and it has from 6 to 15 annular atomses, is 6 to 10 annular atomses in some instances, also refers to contain the alkyl of described aromatic radical. The example of aryl includes but not limited to phenyl, 1-naphthyl, 2-naphthyl and benzyl. Aryl also comprises the group with a plurality of aromatic rings as herein defined, and these a plurality of aromatic rings can condense, as in naphthyl and anthryl, or non-condensed, as in biphenyl and terphenyl. Aryl also refers to carbocyclic rings dicyclo or three rings, and one of them ring is fragrant, and other rings can be saturated, part is undersaturated or fragrant, for example indanyl or tetrahydro naphthyl (tetralin base). As mentioned below, all these aryl also can randomly be replaced.
Term " heterocycle " or " heterocycle " refer to have at least one heteroatomic saturated or the undersaturated monocycle of part, dicyclo or three cyclic groups at least one ring, it has from 3 to 15 atoms, be 3 to 7 in some instances, described hetero atom is selected from O, S or N. Each ring of heterocyclic radical can contain one or two O atom, one or two S atom, one to four N atom, and condition is that heteroatomic sum is four or still less in each ring, and each ring contains at least one carbon atom. The condensed ring of finish dicyclo or three rings heterocyclic radicals can only contain carbon atom, and can be saturated or part is undersaturated. N and S atom are optionally oxidized, and the N atom is optionally quaternized. Heterocycle also refers to contain alkyl described monocycle, dicyclo or three heterocyclic radicals that encircle. The example of heterocyclic radical includes but not limited to, 2-or 3-piperidyl, 2-or 3-piperazinyl, 2-or morpholinyl. As mentioned below, all these heterocyclic radicals also can randomly be replaced.
Term " heteroaryl " refers to the aromatic radical in monocycle or carbocyclic fused ring system, and it has from 5 to 15 annular atomses, is 5 to 10 annular atomses in some instances, and it has at least one hetero atom at least one ring, and described hetero atom is selected from O, S or N. Each ring of heteroaryl can contain one or two O atom, one or two S atom, one to four N atom, and condition is that heteroatomic sum is four or still less in each ring, and each ring contains at least one carbon atom. The condensed ring of finish dicyclo or three rings groups can only contain carbon atom, and can be saturated, part is undersaturated or fragrant. The lone pair electrons of nitrogen-atoms do not have to participate in to finish in the structure of fragrant pi-electron system therein, and the N atom is optionally quaternized or be oxidized to the N-oxide. Heteroaryl also refers to contain the alkyl of described cyclic group. The example of bicyclic heteroaryl includes but not limited to pyrrole radicals, pyrazolyl, pyrazolinyl, imidazole radicals, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl group, isothiazolyl, furyl, thienyl, oxadiazolyl, pyridine radicals, pyrazinyl, pyrimidine radicals, pyridazinyl and triazine radical. The example of bicyclic heteroaryl includes but not limited to indyl, benzothiazolyl, benzoxazolyl, benzo thienyl (benzothienyl), quinolyl, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl, benzopyranyl, indolizine base, benzofuranyl, isobenzofuran-base, chromone base, cumarin base, benzopyranyl, cinnolines base, quinoxalinyl, indazolyl, purine radicals, pyrrolopyridine base, furans and pyridine radicals (furopyridinyl), thienopyridine base, dihydro-iso indolyl and tetrahydric quinoline group. The example of tricyclic heteroaryl includes but not limited to carbazyl, benzindole base (benzindolyl), phenanthroline base (phenanthrollinyl), acridinyl, phenanthridinyl and xanthyl. As mentioned below, all these heteroaryls also can randomly be replaced.
Term " hydroxyl " refers to group-OH.
Term " alkoxyl " refers to group-ORa, R whereinaAlkyl, cycloalkyl or heterocycle. Example includes but not limited to methoxyl group, ethyoxyl, tert-butoxy, cyclohexyloxy and tetrahydro-pyran oxy.
Term " aryloxy group " refers to group-ORb, R whereinbAryl or heteroaryl. Example includes but not limited to phenoxy group, benzyloxy and 2-naphthoxy.
Term " acyl group " refer to group-C (=O)-Rc, R whereincAlkyl, cycloalkyl, heterocycle, aryl or heteroaryl. Example includes but not limited to acetyl group, benzoyl and furoyl.
Term " aminoacyl " expression is derived from amino acid whose acyl group.
Term " amino " refers to-NRdR eGroup, wherein RdAnd ReBe independently selected from the group that is formed by hydrogen, alkyl, cycloalkyl, heterocycle, aryl and heteroaryl. Alternatively, RdAnd ReForm together 3 yuan to 8 yuan heterocycles; it randomly replaces with unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl, unsubstituted heteroaryl, hydroxyl, alkoxyl, aryloxy group, acyl group, amino, acylamino-, carboxyl, carboxyl alkyl, carboxyl aryl, sulfydryl, sulfinyl, sulfonyl, sulfonamido, amidino groups, carbamoyl, guanidine radicals or urea groups, and randomly contains one to three the other hetero atom that is selected from O, S or N.
Term " acylamino-" refer to group-C (=O)-NRfR g, R whereinfAnd RgBe independently selected from the group that is formed by hydrogen, alkyl, cycloalkyl, heterocycle, aryl and heteroaryl. Alternatively, RfAnd RgForm together 3 yuan to 8 yuan heterocycles; it randomly replaces with unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl, unsubstituted heteroaryl, hydroxyl, alkoxyl, aryloxy group, acyl group, amino, acylamino-, carboxyl, carboxyl alkyl, carboxyl aryl, sulfydryl, sulfinyl, sulfonyl, sulfonamido, amidino groups, carbamoyl, guanidine radicals or urea groups, and randomly contains one to three the other hetero atom that is selected from O, S or N.
Term " amidino groups " refers to group-C (=NRh)NR iR j, R whereinhBe selected from the group that is formed by hydrogen, alkyl, cycloalkyl, heterocycle, aryl and heteroaryl; And RiAnd RjBe independently selected from the group that is formed by hydrogen, alkyl, cycloalkyl, heterocycle, aryl and heteroaryl. Alternatively, RiAnd RjForm together 3 yuan to 8 yuan heterocycles; it randomly replaces with unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl, unsubstituted heteroaryl, hydroxyl, alkoxyl, aryloxy group, acyl group, amino, acylamino-, carboxyl, carboxyl alkyl, carboxyl aryl, sulfydryl, sulfinyl, sulfonyl, sulfonamido, amidino groups, carbamoyl, guanidine radicals or urea groups, and randomly contains one to three the other hetero atom that is selected from O, S or N.
Term " carboxyl " refers to group-CO2H。
Term " carboxyl alkyl " refers to group-CO2R k, R whereinkAlkyl, cycloalkyl or heterocycle.
Term " carboxyl aryl " refers to group-CO2R m, R whereinmAryl or heteroaryl.
Term " cyano group " refers to group-CN.
Term " formoxyl " refers to that (=O) H also is represented as-CHO group-C.
Term " halo ", " halogen " or " halide " refer to respectively fluoro, fluorine or fluoride, chloro, chlorine or chloride, bromo, bromine or bromide, and iodo, iodine or iodide.
Term " oxo " refers to divalent group=O, and it replaces two hydrogen atoms to form carbonyl at same carbon.
Term " sulfydryl " refers to group-SRn, R whereinnHydrogen, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl.
Term " nitro " refers to group-NO2。
Term " trifluoromethyl " refers to group-CF3。
Term " sulfinyl " refers to group-S (=O) Rp, R whereinpAlkyl, cycloalkyl, heterocycle, aryl or heteroaryl.
Term " sulfonyl " refer to group-S (=O)2-R q1, R whereinq1Alkyl, cycloalkyl, heterocycle, aryl or heteroaryl.
Term " amino-sulfonyl " refers to group-NRq2-S(＝O) 2-R q3, R whereinq2Hydrogen, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl; And Rq3Alkyl, cycloalkyl, heterocycle, aryl or heteroaryl.
Term " sulfonamido " refer to group-S (=O)2-NR rR s, R whereinrAnd RsBe independently selected from the group that is formed by hydrogen, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl. Alternatively, RrAnd RsForm together 3 yuan to 8 yuan heterocycles; it randomly replaces with unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl, unsubstituted heteroaryl, hydroxyl, alkoxyl, aryloxy group, acyl group, amino, acylamino-, carboxyl, carboxyalkyl, carboxyl aryl, sulfydryl, sulfinyl, sulfonyl, sulfonamido, amidino groups, carbamoyl, guanidine radicals or urea groups, and randomly contains one to three the other hetero atom that is selected from O, S or N.
Term " carbamoyl " refers to formula-N (Rt)-C(＝O)-OR uGroup, R whereintBe selected from hydrogen, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl; And RuBe selected from alkyl, cycloalkyl, heterocycle (heterocylic), aryl or heteroaryl.
Term " guanidine radicals " refers to formula-N (Rv)-C(＝NR w)-NR xR yGroup, R whereinv、R w、 R xAnd RyBe independently selected from hydrogen, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl. Alternatively, RxAnd RyForm together 3 yuan to 8 yuan heterocycles; it randomly replaces with unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl, unsubstituted heteroaryl, hydroxyl, alkoxyl, aryloxy group, acyl group, amino, acylamino-, carboxyl, carboxyalkyl, carboxyl aryl, sulfydryl, sulfinyl, sulfonyl, sulfonamido, amidino groups, carbamoyl, guanidine radicals or urea groups, and randomly contains one to three the other hetero atom that is selected from O, S or N.
Term " urea groups " refers to formula-N (Rz)-C(＝O)-NR aaR bbGroup, R whereinz、R aaAnd RbbBe independently selected from hydrogen, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl. Alternatively, RaaAnd RbbForm together 3 yuan to 8 yuan heterocycles; it randomly replaces with unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl, unsubstituted heteroaryl, hydroxyl, alkoxyl, aryloxy group, acyl group, amino, acylamino-, carboxyl, carboxyalkyl, carboxyl aryl, sulfydryl, sulfinyl, sulfonyl, sulfonamido, amidino groups, carbamoyl, guanidine radicals or urea groups, and randomly contains one to three the other hetero atom that is selected from O, S or N.
It is unsubstituted that term " randomly replacement " is intended to conclusively show concrete group, or by one or more suitable substituting groups replacements, unless optional substituting group is pointed out that clearly this term represents that this group is unsubstituted in this case, or replace with concrete substituting group. As defined above, various groups can be unsubstituted or (being that they are randomly replaced) that replace, unless this paper points out (for example by pointing out that concrete group is unsubstituted) in addition.
When using with term alkyl, cycloalkyl, heterocycle, aryl and heteroaryl; term " replacement " refers to that one or more in the hydrogen atom of group are substituted alkyl, cycloalkyl, heterocycle, aryl or the heteroaryls that base replaces, and described substituting group is independently selected from unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl, unsubstituted heteroaryl, hydroxyl, alkoxyl, aryloxy group, acyl group, amino, acylamino-, carboxyl, carboxyalkyl, carboxyl aryl, halo, oxo, sulfydryl, sulfinyl, sulfonyl, sulfonamido, amidino groups, carbamoyl, guanidine radicals, urea groups and formula-NRccC(＝O)R dd、-NR eeC(＝NR ff)R gg、-OC(＝O)NR hhR ii、-OC(＝O) R jj、-OC(＝O)OR kk、-NR mmSO 2R nnOr-NRppSO 2NR qqR rrGroup, R whereincc、 R dd、R ee、R ff、R gg、R hh、R ii、R jj、R mm、R pp、R qqAnd RrrBe independently selected from hydrogen, not substituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl or unsubstituted heteroaryl; And R whereinkkAnd RnnBe independently selected from unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl or unsubstituted heteroaryl. Alternatively, RggAnd Rhh、R jjAnd RkkOr RppAnd RqqForm together 3 yuan to 8 yuan heterocycles; it randomly replaces with unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl, unsubstituted heteroaryl, hydroxyl, alkoxyl, aryloxy group, acyl group, amino, acylamino-, carboxyl, carboxyalkyl, carboxyl aryl, sulfydryl, sulfinyl, sulfonyl, sulfonamido, amidino groups, carbamoyl, guanidine radicals or urea groups, and randomly contains one to three the other hetero atom that is selected from O, S or N. In addition, for aryl and heteroaryl, term " replacement " comprises the selection that a hydrogen atom of group is replaced by cyano group, nitro or trifluoromethyl.
The condition that replaces is the normal chemical valence that is no more than any atom, and replaces the stable compound of generation. In general, when having the group of replacement form, preferably further do not replace the group of this replacement, if or replace, then substituting group only comprises the group of the replacement of limited quantity, is 1,2,3 or 4 this substituting group in some instances.
When any variable occurred surpassing one time in any composition of this paper or any structural formula, the definition the when definition when it occurs at every turn and other occur at every turn had nothing to do. In addition, the combination of substituting group and/or variable allows, as long as the stable compound of this combination results.
" stable compound " or " stable structure " refer to enough firm in to withstand the compound that is separated to useful purity and is mixed with effective therapeutic agent.
Term " amino acid " refers to common natural (gene code) well known by persons skilled in the art or synthesizing amino acid and common derivative thereof. When being applied to amino acid, " standard " or " proteinogen " refers to 20 amino acid of the gene code of native configurations. Similarly, when being applied to amino acid, " non-natural " or " rare " refers to non-natural, rare or synthetic amino acid whose extensive selection, such as by Hunt, S. at Chemistry and Biochemistry of tge Amino Acids (amino acid whose chemistry and biochemistry), Barrett, G.C. edits, Chapman and Hall:New York, those amino acid of describing in 1985.
About amino acid or amino acid derivativges, term " residue " refers to the group of following formula:
Figure G2008800105877D00341
R wherein AABe amino acid side chain, and in this example n=0,1 or 2.
About the peptide derivant of dipeptides, tripeptides or higher quantity, term " fragment " expression contains the group of two, three or more amino-acid residues respectively.
Term " amino acid side chain " refers to from standard or non-natural amino acid whose any side chain, and is represented as R AAFor example, the side chain of L-Ala is a methyl, and the side chain of Xie Ansuan is a sec.-propyl, and the side chain of tryptophane is a 3-indyl methyl.
The compound that term " agonist " instigates at least some effects of the endogenous ligands of protein, acceptor, enzyme or similar substance to double.
Term " antagonist " refers to the compound of at least some effects of the endogenous ligands of arrestin matter, acceptor, enzyme or similar substance.
Term " growth hormone cinogenic agent " (GHS) refers to animal, particularly in the people, directly or indirectly stimulates or increase any exogenous compound of using and the medicament of the endogenous release of tethelin, tethelin-releasing hormone or somatostatin.The character of GHS can be peptide peptide or non-, and in some instances, it is together with medicament that can be Orally administered.In some instances, this medicament can be induced pulse response.
Term " conditioning agent " refers to give the compound of influence to biological or chemical process or mechanism.For example, conditioning agent can increase, promotes, raises, activates, suppresses, reduces, blocks, prevents, postpones, desensitization, deactivation, downward modulation or influence biological or chemical process or mechanism similarly.Therefore, conditioning agent can be " agonist " or " antagonist ".Exemplary bioprocess or mechanism by the conditioning agent influence include but not limited to that receptors bind and hormone discharge or secretion.Exemplary chemical process or mechanism by the conditioning agent influence include but not limited to catalysis and hydrolysis.
When being applied to acceptor, term " variant " means and comprises dimer, tripolymer, the tetramer, pentamer and the other biological complex body that contains multiple composition.These compositions can be identical or different.
Term " peptide " refers to the main compound of being made up of two or more amino acid that are covalently bound to together.
Term " peptide mimics " refers to be designed to the compound of simulating peptide, but it contains textural difference by one of a plurality of functional groups of adding or replacing peptide, thereby regulate its active or other character, such as solvability, metabolic stability, oral administration biaavailability, lipophilicity, perviousness or the like.This can comprise replace peptide bond, functional group or the like is modified, blocked, adds to side chain.When chemical structure is not derived from peptide, but the activity of simulating peptide, it is commonly called " peptide mimics of non-peptide ".
Term " peptide bond " refer to acid amides [C (=O)-NH-] functionality, have it, single amino acids is mutual covalent bonding in peptide usually.
When term " protecting group " refers to be used in chemical transformation and betides elsewhere in the molecule, prevent that the potential reactive functional groups (such as amine, hydroxyl or carboxyl) on the molecule from carrying out any compound of chemical reaction.Those skilled in the art will know that many these class protecting groups, and the example can be referring to " Protective Groups in Organic Synthesis (protecting group in the organic synthesis) ", TheodoraW.Greene and Peter G.Wuts edit, John Wiley ﹠amp; Sons, New York, the third edition, 1999[ISBN 0471160199].The example of amino protecting group includes but not limited to phthalimido, tribromo-acetyl base, carbobenzoxy-(Cbz), tertbutyloxycarbonyl and Buddha's warrior attendant carbalkoxy.In some embodiments, amino protecting group is the carbamate amino protecting group, and it is defined as the amino protecting group that forms carbamate when combining with amino.In other embodiment, amino carbamate protecting group is allyloxycarbonyl (Alloc), carbobenzoxy-(Cbz) (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), tertbutyloxycarbonyl (Boc) and α, alpha-alpha-dimethyl-3,5-dimethoxy-benzyloxycarbonyl (Ddz).Up-to-date discussion for newer nitrogen-protecting group: Theodoridis, G.Tetrahedron 2000,56,2339-2358.The example of hydroxyl protecting group includes but not limited to ethanoyl, tertiary butyl dimethylsilyl (TBDMS), trityl (Trt), the tertiary butyl and THP trtrahydropyranyl (THP).The example of carboxyl-protecting group includes but not limited to methyl esters, the tert-butyl ester, benzyl ester, TMS ethyl ester and 2,2,2-trichloro ethyl ester.
Term " solid state chemistry " refers to the implementation method of chemical reaction, wherein Fan Ying a kind of composition and polymer materials (as the solid carrier that hereinafter defines) covalent bonding.The reaction method that carries out chemical action on the solid phase is little by little widely known, and is established outside the conventional field of peptide and oligonucleotide chemistry.
Term " solid carrier ", " solid phase " or " resin " refer to be used to carry out the machinery and the chemically stable polymeric matrix of solid state chemistry.It is by " resin ", " P-" or following symbolic representation:
Figure G2008800105877D00361
The example of suitable polymers material includes but not limited to polystyrene, polyethylene, polyoxyethylene glycol, polyoxyethylene glycol grafted polystyrene or (also is called the PEG-polystyrene, TentaGel with the polystyrene of polyoxyethylene glycol covalent bonding TM, Rapp, W.; Zhang, L; Bayer, E. is in Innovations andPersepctives in Solid Phase Synthests.Peptides, Polypeptides andOligonucleotides (innovation in the solid phase synthesis and prospect.Peptide, polypeptide and oligonucleotide) in; Epton, R. edits; SPCC Ltd.:Birmingham, UK; The 205th page), polyacrylic ester (CLEAR TM), poly-(N,N-DMAA) multipolymer of polyacrylamide, urethane, PEGA[polyoxyethylene glycol, Meldal, M.Tetrahedron Lett.1992,33,3077-3080], Mierocrystalline cellulose or the like.These materials can randomly contain extra chemical agent mechanically stablizes this structure to form crosslinked key, for example, and with the crosslinked polystyrene of Vinylstyrene (DVB, normally 0.1-5%, preferably 0.5-2%).As limiting examples, this solid carrier can comprise aminomethyl polystyrene, methylol polystyrene, benzhydrylamine polystyrene (BHA), methyldiphenyl methylamine (MBHA) polystyrene and contain free chemical functional group and (the most commonly is-NH 2Or-OH) be used for other main polymer chains of further deriving or reacting.This term also means " hypertree fat (Ultraresins) " that comprises these functional groups that have at high proportion (" being written into "), such as those (Barth, the M. from polymine and corsslinking molecular preparation; Rademann, J.J.Comb.Chem.2004,6,340-349).When end of synthesis, discard resin usually, can be reused although shown them, as at Frechet, J.M.J.; Haque, K.E.Tetrahedron Lett.1975 is in 16,3055.
In general, the material that is used as resin is insoluble polymkeric substance, but some polymkeric substance has different solvabilities according to solvent, and also can be used for solid state chemistry.For example, polyoxyethylene glycol can use by this way, because it is dissolved in many organic solvents that wherein can carry out chemical reaction, but it is insoluble to other the solvent such as diethyl ether.Therefore, can be in solution homogeneous phase ground processing reaction, by adding diethyl ether the product on the polymkeric substance is precipitated out then, and is processed into solid.This is called as " liquid phase " chemistry.
When using about solid state chemistry, term " linker " refers to merge connection carrier and substrate with the solid carrier covalent linkage, usually in order to allow substrate to discharge the chemical group of (cutting) from solid carrier.Yet it also can be used for giving the stability that is bonded to solid carrier, or only is the interval composition.Many solid carriers are commercially available, and have connected linker.
Be used for the rule of the title of amino acid whose abbreviation and peptide according to the IUPAC-IUB biochemical nomenclature commission, referring to J.Biol.Chem.1972,247,977-983.This file is updated: Biochem.J., 1984,219,345-373; Eur.J.Biochem., 1984,138,9-37; 1985,152,1; Internat.J.Pept.Prot.Res., 1984,24, following p 84; J.Biol.Chem., 1985,260,14-42; Pure Appl.Chem., 1984,56,595-624; Amino Acids andPeptides, 1985,16,387-410; And referring to Biochemical Nomenclature and RelatedDocuments (biological chemical name and pertinent literature), second edition, Portland Press, 1992, the 39-67 pages or leaves.The expansion of this rule is published in JCBN/NC-IUB Newsletter 1985,1986,1989; Referring to Biochemical Nomenclature and Related Documents (biological chemical name and pertinent literature), second edition, Portland Press, 1992, the 68-69 pages or leaves.
Term " significant quantity " or " effectively " are to be used for showing causing by clinical trial and evaluation, patient and observing, and/or the dosage of the alleviation of the symptom of pointed disease of similar approach or illness, and/or cause the dosage of detectable biological or chemical activity change.Detectable variation can be by the mechanism or the process that are detected and/or further quantitatively be used to be correlated with by those skilled in the art.Understand as this area is common, dosage will change according to route of administration, symptom and patient's body weight, and changes according to the compound of being used.
" combination " use two or more compounds mean two kinds of compounds enough approaching time the place use, a kind of existence of compound changes alternative biological effect.These two kinds of compounds are (simultaneously) or sequentially use side by side.Can be by before using, mixing these compounds, perhaps by on identical time point, but at the different regions of anatomy or use different route of administration to use these compounds, carry out using simultaneously.As used herein, phrase " is used (concurrentadministration) " simultaneously, " combined administration ", " using (simultaneous administration) simultaneously " or " being applied simultaneously " mean compound and use on identical time point or follow hard on mutually and use.In the later case, two compounds are used at enough approaching time place, and what difference is observed result do not have with the result who is realized when compound when identical time point is used.
In addition, compound of the present invention can with another kind of compound (such as specific medicament) combined administration in one way, this mode is used compound of the present invention and specific medicament before being encompassed in begin treatment, so that prevent and/or handle the influence of special medicament.
Term " pharmaceutical activity metabolite " is to be used for meaning the pharmacologically active product that is produced by particular compound metabolism in vivo.
Term " solvate " is the pharmaceutically acceptable solvate forms that is used for meaning particular compound, and it has kept the biopotency of this compound.The example of solvate comprises and is not limited to the combination of compound of the present invention and water, Virahol, ethanol, methyl alcohol, DMSO, ethyl acetate, acetate or thanomin.
1. compound
Novel macrocylc compound of the present invention comprises the macrocylc compound that comprises element structure, and this element structure comprises tethers (tether) composition, and it stands cyclisation to form this macrocylc compound.Element structure can comprise amino acid (standard with non-natural), alcohol acid, diazanyl acid, azepine amino acid, such as the specific part of those parts that in introducing peptide surrogate and isostere, work, and tethers composition as described herein.
The present invention includes isolated compound.Isolated compound refers to such compound: in some embodiments, comprise this compound of at least 10%, at least 25%, at least 50% or at least 70% in the mixture.In some embodiments, this compound, its pharmacy acceptable salt or the pharmaceutical composition that contains this compound are when when tested, show statistically evident combination and/or antagonistic activity to human growth hormone's releasing peptide receptor in biological assay.
At compound, salt or solvate is under the solid situation, it will be understood by those skilled in the art that crystal or polymorphic that compound, salt and the solvate of invention can be different exist, and expect that all these are in the scope of the present invention and concrete structure formula.
Compound disclosed herein can have asymmetric center.The compound of invention can be used as one steric isomer, racemic modification, and/or the mixture of enantiomorph and/or diastereomer exists.Expect all these one steric isomers, racemic modification and its mixture within the scope of the invention.Yet in specific embodiment, the compound of invention uses with optically pure form.As used herein, term " S " and " R " configuration be as by at the E chapters and sections, the IUPAC 1974 of Fundamentals of Stereochemistry (stereochemistry basis) recommend (Pure Appl.Chem.1976,45,13-30) defined.
Unless be described as concrete orientation in addition, the present invention includes all stereoisomeric forms in any ratio.This compound can be prepared as the mixture of single steric isomer or steric isomer.Non-racemization form can obtain by synthetic or fractionation.For example, compound can be split as the composition enantiomorph by standard technique, and is for example right through the formation formation diastereomer of salt.This compound also can by with the incompatible fractionation of chirality part covalent linkage.Then, diastereomer can split by chromatographic separation and/or Crystallization Separation.In the example of chiral auxiliary(reagent) part, it can be removed after a while.As an alternative, this compound can split by using chiral chromatography.In some cases, also can use enzyme process to split.
Such as those skilled in the art usually understanding, " optical purity " compound is the compound that only contains single enantiomer.As used herein, term " optical activity " is to be used for expression to comprise at least a enantiomorph enough excessive to another kind of enantiomorph, makes the compound of mixture Plane of rotation polarized light.Optically active compound has the ability of rotatory polarization optical plane.A kind of enantiomorph is to the excessive enantiomeric excess (e.e.) that is typically expressed as of another kind of enantiomorph.In describing optically active compound, prefix D and L or R and S are used to represent the absolute configuration of molecule about its chiral centre.Prefix " d " and " l " or (+) and (-) are used to represent the opticity (promptly passing through the direction of optically active compound rotatory polarization optical plane) of compound." l " or (-) prefix designates compound are left-handed (promptly left or counterclockwise rotatory polarization optical plane), and " d " or (+) prefix to mean compound be dextral (promptly to the right or clockwise direction rotatory polarization optical plane).The symbol (-) of opticity and (+) are irrelevant with the absolute configuration R and the S of molecule.
Compound of the present invention with pharmacological property of expectation will be to have optically actively, and can mainly be made up of the individual isomer of at least 90% (80%e.e.), at least 95% (90%e.e.), at least 97.5% (95%e.e.) or at least 99% (98%e.e.).
Similarly, many geometrical isomers of two keys and analogue also can be present in the compound disclosed herein, and unless otherwise indicated, all these stable isomer comprise in the present invention.The present invention also comprises the tautomer and the rotational isomer of compound.
Use the following symbol on right side to refer to replace institute with the substituent R of determining One or more hydrogen atoms of the ring of indication.
Use following symbolic representation singly-bound or optional two keys:
Embodiment of the present invention further provide the intermediate that forms by synthetic method as herein described so that the compound of formula I and/or formula II to be provided.This intermediate can have the effectiveness that conduct is used for the therapeutical agent of a series of indications as herein described and/or is used for the reagent of further synthetic method and reaction.
2. synthetic method
Compound of the present invention can use conventional soln synthetic technology or solid state chemistry method to synthesize.Among both, structure comprises four-stage: the first, and segmental member, its recognition component that comprises the biological target acceptor add a tethers part that is mainly used in control and constrained conformation.In subordinate phase, use standard chemical to transform, these members are assembled into together usually in a sequential manner.Then, the precursor that comes self-assembly in the phase III cyclisation so that macrocyclic structure to be provided.At last, the quadravalence section that comprises the cyclisation aftertreatment of removing protecting group and optional purifying provides the final compound of expectation.The synthetic method of the macrocyclic structure of this general type is described in International Patent Application WO 01/25257, WO 2004/111077, WO 2005/012331 and WO 2005/012332, comprises that purge process is described in WO2004/111077 and WO 2005/012331.Also referring to U.S. Patent Application Serial Number 11/149,512 and 11/149,731.
In some embodiments of the present invention, but the macrocylc compound priority of use before the definition solvable or insoluble polymeric matrix on solid state chemistry synthesize.For solid state chemistry, must carry out the preproduction phase, it comprises first member is connected, and is also referred to as " being written into " to resin.Be used for resin of the present invention and preferentially the linker partial L be connected to it.By standard reaction method known in the art, be used to form any one of many reaction conditionss of ester or amido linkage such as exploitation, these linkers are connected to suitable free chemical functionality on the base resin (base resin), normally alcohol or amine are although other materials also are possible.Design linker parts more of the present invention so that it in the process that is commonly referred to as " cyclisation-release ", cuts from resin when forming big ring.(vanMaarseveen, J.H.Solid phase synthesis of heterocycles by cyclization/cleavagemethodologies (by cyclisation/cutting method solid phase synthesis heterocycle).Comb.Chem.HighThroughput Screen.1998,1,185-214; Ian W.James, Linkers for solid phaseorganic synthesis (linker of solid phase organic synthesis).Tetrahedron 1999,55,4855-4946; Eggenweiler, H.-M.Linkers for solid-phase synthesis of smallmolecules:coupling and cleavage techniques (the micromolecular linker of solid phase synthesis: coupling and cutting technique).Drug Discovery Today 1998,3,552-560; Backes, B.J.; Ellman, J.A.Solid support linker strategies (solid carrier linker strategy).Curr.Opin.Chem.Biol.1997，1，86-93。About compound of the present invention, 3-propane thioic acid linker is useful especially.(Hojo，H.；Aimoto，S.Bull.Chem.Soc.Jpn.1991，64，111-117；Zhang，L.；Tam，J.J.Am.Chem.Soc.1999，121，3311-3320。)
This process provides the material of higher degree, because only the ring-type product discharges from solid carrier, and not as understand the spot at solution in mutually and linear precursor impurity occur.Use known or standard reaction is chemical all members and tethers der group are dressed up linear precursor after, by suitable nucleophilic functionality the intramolecularly of the alkali mediation of the carbonyl that is connected to this linker is attacked and to be made and form acid amides or ester bond, the ring structure of (scheme 1) shown in it is finished, described nucleophilic functionality is the part of tethers member.Also can use the similar approach that is suitable for the solution phase, because it may will be more suitable in fairly large application.
Scheme 1. cyclisation-release strategy
Figure G2008800105877D00421
Although this description has represented to be used for the approach of one of the inventive method exactly, the thioesters strategy, another method of the present invention, promptly closed loop disproportionation (RCM) is undertaken by the route of improvement, and the tethers composition is in fact assembled during cyclisation step in this route.Yet, in the RCM method, carry out the assembling of member in order equally, cyclisation subsequently (and if solid phase discharges from resin).Need extra cyclisation post-processing step removing the specific by product of RCM reaction, but remaining with aftertreatment be used for thioesters strategy or mode that similarly the cyclisation strategy of alkali mediation is identical and carry out.
In addition, should be understood that each step that comprises method provided herein can carry out independently, or at least two steps can be combined.In addition, when carrying out independently or in combination, comprise that each step of method provided herein can be carried out under identical temperature or different temperature, and do not break away from instruction of the present invention.
Novel macrocylc compound of the present invention comprises the macrocylc compound that is formed by novel method, and this method comprises that the cyclisation element structure contains the macrocylc compound of tethers composition as herein described with formation.Therefore, the invention provides the method for producing compound of the present invention, it comprises (a) assembled component structure; (b) chemical conversion element structure; (c) cyclisation comprises the element structure of tethers composition, (d) removes protecting group and (e) product that obtains from step (d) of purifying randomly from element structure.In some embodiments, the assembling of element structure can be an order.In further embodiment, use conventional soln synthetic technology or solid state chemistry technology to carry out synthetic method.
A. amino acid
Amino acid; the amino acid of Boc-and Fmoc-protection and the derivative of side chain protected; comprise those N-methylamino acids and non-natural amino acid; be from commercial supplier [AdvancedChemTech (Louisville for example; KY; USA); Astatech (Bristol, PA, USA); Bachem (Bubendorf; Switzerland); ChemImpex (Wood Dale; IL, USA); Novabiochem (Subsidiary Company of Merck KGaA, Darmstadt; Germany); PepTech (Burlington; MA, USA); Synthetech (Albany, OR; USA)] obtain, or by standard method synthetic well known by persons skilled in the art.Ddz-amino acid be from Orpegen (Heidelberg, Germany) or Advanced ChemTech (Louisville, KY, USA) the commercial acquisition, or use the standard method to utilize Ddz-OPh or Ddz-N3 synthetic.(Birr，C.；Lochinger，W.；Stahnke，G.；Lang，P.Justus?Liebigs?Ann.Chem.1972，763，162-172。) Bts-amino acid is synthetic by currently known methods.(Vedejs，E.；Lin，S.；Klapara，A.；Wang，J.J.Am.Chem.Soc.1996，118，9796-9797。Also having WO 01/25257, WO 2004/111077) N-alkyl amino acid, particularly N-methylamino acid obtain from a plurality of suppliers (Bachem, Novabiochem, Advanced ChemTech, ChemImpex) are commercial.In addition, N-alkylamino acid derivative obtains through the document method.(Hansen，D.W.，Jr.；Pilipauskas，D.J.Org.Chem.1985，50，945-950。)
B. tethers
Tethers is that the method from before be described in International Patent Application WO 01/25257, WO 2004/111077, WO 2005/012331 and PCT/US2007/017905 obtains.Also referring to U.S. Patent Application Serial Number 11/149,512 and 11/149,731.The preparation of other tethers provides in an embodiment.
Below be the tethers intermediate that is used for synthetic The compounds of this invention:
Figure G2008800105877D00441
Figure G2008800105877D00451
C. solid phase and solution technology mutually
The concrete solid phase technique that is used for synthetic macrocylc compound of the present invention has been described in WO01/25257, WO 2004/1111077, WO 2005/012331 and WO 2005/012332.Solution is combined to route, comprises the method that is suitable for fairly large production, is described in No. the 2006/025566th, U.S. Patent Application Publication and US 2007/0021331.
Yet in some cases, the unstable of protecting group has hindered the use that is used for the standard alkaline type medium of cyclisation in the thioesters strategy discussed above.In these cases, one of two kinds of acid processes are used to provide big cyclisation under acidic conditions.A kind of method is used HOAc, and another kind of method is used HOAt (scheme 2).
After carrying out to Ddz on the tethers or Boc group deprotection base, resin DCM (2x), DCM-MeOH (1: 1,2x), DCM (2x) and DIPEA-DCM (3: 7,1x) washing in order.With resin under vacuum dry 10 minutes, join immediately then in degassing DMF (5%v/v) solution of HOAc.Reaction mixture is stirred under 50-70 ℃ of O/N.Filter resin, with the THF washing, and the filtrate that merges of decompression (water pump, oil pump then) evaporation and washings are to obtain big ring.
Scheme 2: optional cyclization method
Figure G2008800105877D00461
Following table provides about being used to uses standard method to synthesize the information of the member of representative compounds of the present invention.These can be directly used in solid phase synthesis.Be combined to for solution, the protection strategy of improveing from the strategy of being set forth is generally used for allowing to use assemblage method (convergent approach).The other synthetic details that the solution of representative macrocylc compound of the present invention makes up mutually provides in an embodiment.
Figure G2008800105877D00471
Figure G2008800105877D00491
Figure G2008800105877D00501
Figure G2008800105877D00511
Figure G2008800105877D00521
Figure G2008800105877D00531
Figure G2008800105877D00541
Figure G2008800105877D00551
Following table provides the analytical data of the analytical data representative compounds of the present invention of representative compounds of the present invention
Compound number Molecular formula MW calculated value (g/mol) MS[(M+H)+] measured value
??801 ??C31H48N4O4 ??540.7 ??541
??802 ??C28H42N4O4 ??498.7 ??499
??803 ??C31H40N4O5 ??548.7 ??549
??807 ??C28H44N4O4 ??500.7 ??501
??808 ??C31H42N4O5 ??550.7 ??551
??809 ??C29H37N4O5F ??540.6 ??541
??810 ??C26H39N4O4F ??490.6 ??491
??813 ??C26H39N4O4F ??490.6 ??491
??816 ??C26H38N4O4F2 ??508.6 ??509
??818 ??C29H36N4O5F2 ??558.6 ??559
??819 ??C28H44N4O4 ??500.7 ??501
??820 ??C31H42N4O5 ??550.7 ??551
??822 ??C27H41N4O4F ??504.6 ??505
??825 ??C27H48N4O4 ??492.7 ??493
??826 ??C30H46N4O5 ??542.7 ??543
??828 ??C30H54N4O4 ??534.8 ??535
??829 ??C33H52N4O5 ??584.8 ??585
??831 ??C30H52N4O4 ??532.8 ??533
??832 ??C30H45N4O5F ??560.7 ??561
??833 ??C28H50N4O4 ??506.7 ??507
??851 ??C30H40N4O4 ??520.7 ??521
??853 ??C30H41N4O4F ??540.7 ??541
??854 ??C30H38N4O4F2 ??556.6 ??557
??855 ??C31H43N4O4F ??554.7 ??555
??856 ??C31H42N4O4F2 ??572.7 ??573
??857 ??C30H41N4O4F ??540.7 ??541
??858 ??C30H42N4O4 ??522.7 ??523
??859 ??C30H42N4O4 ??522.7 ??523
??860 ??C30H40N4O4 ??520.7 ??521
??862 ??C30H39N4O4Cl ??555.1 ??555
??863 ??C30H41N4O4Cl ??557.1 ??557
??864 ??C29H36N4O4FCl ??559.1 ??559
??865 ??C29H37N4O4F ??524.6 ??525
??866 ??C31H44N4O5 ??552.7 ??553
??867 ??C31H42N4O5 ??550.7 ??551
??869 ??C29H39N4O4Cl ??543.1 ??543
??870 ??C30H42N4O4 ??522.7 ??523
??871 ??C30H42N4O4 ??522.7 ??523
??872 ??C29H37N4O4Cl ??541.1 ??541
??873 ??C29H37N4O4Cl ??541.1 ??541
??874 ??C31H40N4O4 ??532.7 ??533
??876 ??C30H39N4O4F ??538.7 ??539
??877 ??C30H38N4O4FCl ??573.1 ??573
??878 ??C31H43N4O4Cl ??571.2 ??571
??923 ??C32H46N4O4 ??550.7 ??551
??934 ??C30H42N4O5 ??538.7 ??539
??935 ??C30H38N4O4F2 ??556.6 ??557
??936 ??C30H38N4O4FCl ??573.1 ??573
??937 ??C30H38N4O4F2 ??556.6 ??557
??938 ??C30H38N4O4FCl ??573.1 ??573
??939 ??C31H44N4O5 ??552.7 ??553
??944 ??C30H38N4O4FCl ??573.1 ??573
??945 ??C30H38N4O4Cl2 ??589.6 ??589
??946 ??C31H39N4O4F ??550.7 ??551
??947 ??C31H39N4O4Cl ??567.1 ??567
??950 ??C30H37N4O4F3 ??574.6 ??575
??951 ??C30H37N4O4F2Cl ??591.1 ??591
??954 ??C30H41N4O4F ??540.7 ??541
??965 ??C32H43N4O4F ??566.7 ??567
??966 ??C32H42N4O4FCl ??601.2 ??601
??968 ??C27H42N4O4 ??486.6 ??487
??969 ??C28H46N4O4 ??502.7 ??503
??972 ??C29H39N5O4 ??521.7 ??522
??973 ??C29H38N5O4F ??539.6 ??540
??974 ??C30H42N5O4F ??555.7 ??556
??975 ??C29H39N5O4 ??521.7 ??522
??976 ??C30H43N5O4 ??537.7 ??538
??977 ??C29H39N5O4 ??521.7 ??522
??978 ??C30H43N5O4 ??537.7 ??538
??979 ??C27H41N4O4F ??504.6 ??505
??981 ??C28H45N4O4F ??520.7 ??521
??982 ??C33H45N4O4F ??580.7 ??581
??986 ??C25H39N5O4 ??473.6 ??474
??987 ??C26H43N5O4 ??489.7 ??490
??988 ??C28H37N5O5 ??523.6 ??524
??989 ??C30H40N4O5 ??536.7 ??537
??991 ??C30H39N4O5F ??554.7 ??555
??992 ??C29H41N5O5 ??539.7 ??540
??993 ??C31H44N4O5 ??552.7 ??553
??994 ??C31H43N4O5F ??570.7 ??571
??995 ??C26H35N5O4S ??513.7 ??514
??996 ??C27H39N5O4S ??529.7 ??530
??997 ??C30H41N4O5F ??556.7 ??557
??998 ??C28H38N5O5F ??543.6 ??544
??999 ??C26H41N5O4 ??487.6 ??488
??1000 ??C27H45N5O4 ??503.7 ??504
??1003 ??C31H41N4O4F ??552.7 ??553
??1005 ??C31H41N4O4F ??552.7 ??553
??1006 ??C27H41N4O4Cl ??521.1 ??521
??1007 ??C30H38N4O4FCl ??573.1 ??573
??1008 ??C27H39N4O4F ??502.6 ??503
??1009 ??C31H39N4O4F ??550.7 ??551
??1010 ??C31H41N4O4F ??552.7 ??553
??1011 ??C31H41N4O4F ??552.7 ??553
??1014 ??C27H42N4O4 ??486.6 ??487
??1015 ??C28H42N4O4 ??498.7 ??499
??1016 ??C31H39N4O4F ??550.7 ??551
??1017 ??C31H41N4O4F ??552.7 ??553
??1018 ??C31H41N4O4F ??552.7 ??553
??1019 ??C27H40N4O4 ??484.6 ??485
??1020 ??C30H37N4O4F ??536.6 ??537
??1021 ??C25H39N5O4 ??473.6 ??474
??1022 ??C26H43N5O4 ??489.7 ??490
??1023 ??C29H39N5O5 ??537.7 ??538
??1024 ??C31H40N4O5 ??548.7 ??549
??1025 ??C30H38N4O5 ??534.6 ??535
??1026 ??C30H43N5O5 ??553.7 ??554
??1027 ??C29H38N5O4F ??539.6 ??540
??1028 ??C29H39N5O4 ??521.7 ??522
??1029 ??C30H42N5O4F ??555.7 ??556
??1030 ??C30H43N5O4 ??537.7 ??538
??1031 ??C28H37N5O4 ??507.6 ??508
??1032 ??C29H40N5O5F ??557.7 ??558
??1033 ??C31H41N4O4F ??552.7 ??553
??1034 ??C31H41N4O4F ??552.7 ??553
??1035 ??C32H43N4O4F ??566.7 ??567
??1036 ??C25H36N4O6 ??488.6 ??489
??1038 ??C31H39N4O4F3 ??588.7 ??589
??1039 ??C30H38N4O4Cl2 ??589.6 ??589
??1040 ??C30H38N4O4F2 ??556.6 ??557
??1041 ??C30H37N4O4F3 ??574.6 ??575
??1042 ??C30H35N4O4F5 ??610.6 ??611
??1043 ??C28H44N4O4 ??500.7 ??501
??1044 ??C27H41N4O4F ??504.6 ??505
??1045 ??C30H46N4O4 ??526.7 ??527
??1046 ??C29H44N4O4 ??512.7 ??513
??1047 ??C29H44N4O4 ??512.7 ??513
??1048 ??C26H38N4O4 ??470.6 ??471
??1049 ??C30H39N4O5F ??554.7 ??555
??1050 ??C25H38N4O5 ??474.6 ??475
??1052 ??C30H45N4O4F ??544.7 ??545
??1053 ??C30H38N4O5Br2 ??694.5 ??695 *
??1058 ??C27H42N4O5 ??502.6 ??503
??1061 ??C29H47N5O4 ??529.7 ??530
??1062 ??C32H45N5O5 ??579.7 ??580
??1065 ??C32H41N4O6F ??596.7 ??597
??1066 ??C32H40N4O6Br2 ??736.5 ??737 *
??1068 ??C31H42N4O5 ??550.7 ??551
??1069 ??C31H42N4O5 ??550.7 ??551
??1071 ??C32H43N4O4F ??566.7 ??567
??1072 ??C31H42N4O5 ??550.7 ??551
??1074 ??C30H39N5O5 ??549.7 ??550
??1075 ??C27H41N5O4 ??499.6 ??500
??1076 ??C31H41N5O5 ??563.7 ??564
??1078 ??C28H36N5O5F ??541.6 ??542
??1079 ??C29H39N5O5 ??537.7 ??538
??1080 ??C29H39N5O5 ??537.7 ??538
??1081 ??C30H41N5O5 ??551.7 ??552
??1082 ??C30H41N5O5 ??551.7 ??552
??1083 ??C30H40N4O5 ??536.7 ??537
??1084 ??C27H42N4O4 ??486.6 ??487
??1085 ??C30H40N4O5 ??536.7 ??537
??1086 ??C27H42N4O4 ??486.6 ??487
??1087 ??C30H41N5O5 ??551.7 ??552
??1088 ??C27H43N5O4 ??501.7 ??502
??1089 ??C30H41N5O5 ??551.7 ??552
??1090 ??C26H38N4O6 ??502.6 ??503
??1098 ??C31H43N5O5 ??565.7 ??566
??1099 ??C30H48N4O4 ??528.7 ??529
??1100 ??C29H35N4O4F3 ??560.6 ??561
??1101 ??C30H40N4O5 ??536.7 ??537
??1103 ??C29H38N4O5 ??522.6 ??523
??1104 ??C30H39N4O5F ??554.7 ??555
??1105 ??C34H46N4O5 ??590.8 ??591
??1106 ??C26H46N4O4 ??478.7 ??479
??1107 ??C28H50N4O4 ??506.7 ??507
??1108 ??C33H46N4O5 ??578.7 ??579
??1109 ??C29H36N4O4F2 ??542.6 ??543
??1110 ??C29H37N4O5F ??540.6 ??541
??1111 ??C26H39N4O4F ??490.6 ??491
??1112 ??C29H45N4O4F ??532.7 ??533
??1113 ??C32H43N4O5F ??582.7 ??583
??1114 ??C29H50N4O4 ??518.7 ??519
??1115 ??C30H46N4O5 ??542.7 ??543
??1116 ??C28H48N4O4 ??504.7 ??505
??1117 ??C30H39N6O4F ??566.7 ??567
??1118 ??C29H44N4O5 ??528.7 ??529
??1119 ??C32H44N4O5 ??564.7 ??565
Annotate
*[(M+2+H) +]
Molecular formula and molecular weight be through ActivityBase software (ID Business Solutions, Ltd., Guildford, Surre y UK) automatically calculates from structure.
2.M+H the use standard method is analyzed acquisition from LC-MS.
3. all analyses are carried out on the material behind the preparation purifying.
3. biological method
Estimate compound of the present invention and the interactional ability of human growth hormone's releasing peptide receptor.Can use competitive radioligand in conjunction with mensuration, fluorometric assay or aequorin functional examination.These methods can high-throughout mode be carried out to allow to estimate simultaneously chemical compound lot.
Concrete measuring method (the United States Patent (USP) the 6th that is used for people (GHS-R1a), pig and rat GHS-acceptor, 242, No. 199, international patent application no WO 97/21730 and 97/22004), and the concrete measuring method (United States Patent (USP) the 6th of dog GHS-acceptor, 645,726), and their differentiate that general purposes in its agonist and the antagonist is known.
Be used for determining the also description hereinafter of appropriate method of compound of the present invention and interactional functionally active of human growth hormone's releasing peptide receptor and activity in vivo.In addition, the method for setting up in this area can be used for determining other important parameters concerning using as medicament, such as pharmacokinetics, Caco-2 perviousness, plasma proteins combination.
A. competitive radioligand is in conjunction with measuring (ghrelin receptor)
Competitive binding assay to human growth hormone secretogogue acceptor (hGHS-R1a) can carry out similarly by the mensuration of describing in the document.(Bednarek, people J.Med.Chem.2000 such as M.A., 43,4370-4376; Palucki, people Bioorg.Med.Chem.Lett.2002 such as B.L., 11,1955-1957.) also referring to U.S. Patent Application Serial Number 11/149,512 and 11/149,731.Representative compounds of the present invention shows in following examples in conjunction with active ghrelin receptor.
B. aequorin functional examination (ghrelin receptor)
Functionally active with the The compounds of this invention GHS-R1a receptors bind that found can use the method for describing in the document to determine that it also can be used as the active primary dcreening operation of ghrelin receptor of high-throughput mode.Also referring to U.S. Patent Application Serial Number 11/149,512 and 11/149,731.(LePoul, people J.Biomol.Screen.2002 such as E., 7,57-65; Bednarek, people J.Med.Chem.2000 such as M.A., 43,4370-4376; Palucki, people Bioorg.Med.Chem.Lett.2001 such as B.L., 11,1955-1957.) representative compounds of the present invention provides in an embodiment to the functionally active of ghrelin receptor.
C.IP1 functional examination (ghrelin receptor)
Compound of the present invention is renderd a service the HEK-293 cell that also can use stably express people GHS-R1a as the external function of the activator of the signal transduction path of ghrelin receptor mediation and is determined.Method
Use the HEK-293 clone of stably express human growth hormone releasing peptide receptor to test representative compounds of the present invention.Via the multiple concentration in the scope that is used in 0.001-1000nM, common 7-8, at 37 ℃ of following incubated cells after 30 minutes, inositol-1-phosphoric acid ester (IP1), receptor activation is monitored in the formation of the metabolite of a kind of Gq-protein/Phospholipase C approach.Stop hatching by adding lysis buffer.Before reading fluorescence, allow lysate at room temperature to use IP1-d2 and anti-IP1 cryptate compound (Anti-IP1-cryptate) to hatch 1 hour.Each data point is represented the mean value ± SD of four independent experiments.Inositol-1-phosphoric acid ester (IP1) is passed through IP-One
Figure G2008800105877D00651
Measure (CisBio, Bedford, MA, USA) quantitative.This test has made up the competitive immunometric assay as indicator based on the IP1 of anti-IP1MAb that uses the cryptate compound mark and d2 mark.When lacking endogenous IP1, cryptate compound Mab and IP-d2 interact, and generation can quantitative FRET (fluorescence energy transfer) signal.
The result
The result of this mensuration of two kinds of exemplary compounds of the present invention shows in Fig. 1.
D. the pharmacokinetic analysis of representative compounds of the present invention
The pharmacokinetics behavior of compound of the present invention can be determined by well known to a person skilled in the art method.(at Goodman ﹠amp; The The Pharmacological Basis ofTherapeutics (pharmacological basis of treatment) of Gilman, the 10th edition, Hardman, J.G.; Limbird, L.E. edit, McGraw Hill, Columbus, OH, 2001, Wilkinson in the 1st chapter, G.R. " Pharmacokinetics:The Dynamics of Drug Absorption, Distribution, andElimination (pharmacokinetics: the kinetics of drug absorption, distribution and elimination) ".) following method is used to study the pharmacokinetic parameter (eliminating transformation period, total plasma clearance or the like) of intravenously, subcutaneous and Orally administered The compounds of this invention.Also referring to U.S. Patent Application Serial Number 11/149,512 and 11/149,731, and international patent application no PCT/US2007/017905.The oral administration biaavailability data of representative compounds of the present invention provide in following embodiment.
E. the stomach emptying in the fasting rat model
In order to check in model compound of the present invention to the influence of gastroparesis, assessing compound may influence the stomach emptying of fasting rat.This model is used for determining that compound of the present invention promotes the possibility of motion the fasting rat.
Method
1. the meals (2mL) of methylcellulose gum (2%) are provided to the rat (male, Wistar, 200g, n=5/ group) of overnight fast by intragastric gavage.Meals are with phenol red (0.05%) mark.
2. behind the feeding, use test substances (with different concentration administrations by oral gavaging (time=0) immediately, normally 1,3,10,30mg/kg), vehicle and positive control (metoclopramide, a kind of present regulation be used for the treatment of the GI illness, comprise the 5-HT part and the activator of gastroparesis).
3.15 put to death animal after minute; Shift out stomach immediately, and in 0.1N NaOH, stir evenly also centrifugal.
By colorimetry at the 560nm place quantitatively residual under one's belt always phenol red.
5.30% or the increase (with vehicle contrast contrast) of higher stomach emptying be considered to significant.
6. application one-way analysis of variance, Dunnet statistical test afterwards (Dunnet ' s post-hocstatistical test).
The result
The representative compounds of the present invention of using this rat model provides in following examples the influence of stomach emptying.
F. stomach emptying in the rat model of postoperative ileus and intestines transportation
The clinical correlation model of this POI is that the model modification by Kalff forms.(Kalff，J.C.；Schraut，W.H.；Simmons，R.L.；Bauer，A.J.Ann.Surg.1998，228，652-663。) other known models also can be used for studying the effect of compound of the present invention.(Trudel，L.；Bouin，M.；Tomasetto，C.；Eberling，P.；St-Pierre，S.；Bannon，P.；L’Heureux，M.C.；Poitras，P.Peptides?2003，24，531-534；(b)Trudel，L.；Tomasetto，C.；Rio，M.C.；Bouin，M.；Plourde，V.；Eberling，P.；Poitras，P.Am.J.Physiol.2002，282，G948-G952。)
Animal
1. rat, Sprague-Dawley, male ,～300g.
2. fasting O/N before studying.
Postoperative ileus (POI) induces
1. isoflurane (isoflurane) anesthesia under the aseptic condition.
2. center line abdominal incision.
3. take out intestines and caecum, and preserve moisture with salt solution.
4. handle them with wet cotton applicator (cotton applicator) along the total length of intestines and caecum, be similar to " runnings of intestines " in the clinical setting.The time remaining of this process 10 minutes.
5. intestines are put back in the belly lightly, and under aseptic condition, abdominal wound are sewed up.
Administration
1. rat is recovered from isoflurane anesthesia.
2. use test compounds (or vehicle) via the jugular vein conduit intravenously of previous implantation.
3. gavage in the stomach immediately and use radioactivity 99mThe methylcellulose gum of Tc mark (2%), t=0.
Experiment
1. located at t=15 minute, use CO 2Make animal euthanasia.
Stomach and along the each several part of the 10cm of small intestine by ligation immediately, excise and place pipe to be used for measuring at gamma counter 99mTc.
3. the transportation of stomach emptying and small intestine is measured by computational geometry mean number.
Geometric mean=∑ (% gross activity X part number)/100
G. tethelin is to the response of test compounds
Similarly, can in many animal models, test the influence that compound of the present invention discharges GH.For example, rat (Bowers, C.Y.; Momany, F.; Reynolds, G.A.; Chang, D.; Hong, A.; Chang, K.Endocrinology 1980,106,663-667), dog (Hickey, G.; Jacks, T.; Judith, F.; Taylor, J.; Schoen, W.R.; Krupa, D.; Cunningham, P.; Clark, J.; Smith, R.G.Endocrinology 1994,134,695-701; Jacks, T.; Hickey, G.; Judith, F.; Taylor, J.; Chen, H.; Krupa, D.; Feeney, W.; Schoen, W.R.; Ok, D.; Fisher, M.; Wyvratt, M.; Smith, R.J.Endocrinology 1994,143,399-406; Hickey, G.J.; Jacks, T.M.; Schleim, K.D.; Frazier, E.; Chen, H.Y.; Krupa, D.; Feeney, W.; Nargund, R.P.; Patchett, A.A.; Smith, R.G.J.Endocrinol.1997,152,183-192) and pig (Chang, C.H.; Rickes, E.L.; Marsilio, F.; McGuire, L.; Cosgrove, S.; Taylor, J.; Chen, H.Y.; Feighner, S.; Clark, J.N.; Devita, R.; Schoen, W.R.; Wyvratt, M.; Fisher, M.; Smith, R.G.; Hickey, G.Endocrinology 1995,136,1065-1071; (b) Peschke, B.; Hanse, B.S.Bioorg.Med.Chem.Lett.1999,9,1295-1298) all be successfully used to the effect of research GHS in the body, and similarly will be applied to study of the influence of ghrelin agonist the GH level.After suitably using compound of the present invention, the measurement of the GH level of ghrelin can use radioimmunoassay to carry out through standard method well known by persons skilled in the art in the blood plasma.(Deghenghi, people Life Sciences 1994,54 such as R., 1321-1328.) with the test substances that contains the radioactivity mark to animals administer after, can use the combination of WBA research to tissue.(Ahnfelt-
Figure G2008800105877D00681
I.; Nowak, J.; Olsen, U.B.Do growth hormone-releasingpeptides act as ghrelin secretagogues? can (growth hormone-releasing peptide be as the ghrelin secretogogue?) Endocrine 2001.14,133-135.)
Following method is used for determining that tethelin (GH) is to whole body or concentrate the temporal mode and the value of the response of the test compounds that (centrally) use.Similarly method can be used for other suitable animal models, such as dog and cynomolgus monkey.
Be used for interior administration and the sampling procedure of studying of body that GH discharges
Bull Sprague Dawley rat (225-300g) is from Charles River Canada (St.Constant, Canada) buy, and support separately and be in 12 hours, dark circulation in 12 hours (is illuminated the time: in the chamber of controlled temperature 0600-1800) (22 ± 1 ℃) and humidity.(Ralston Purina Co., St.Louis MO) can freely obtain with tap water the Purina rat feed.For these research, (50mg/kg, ip) anesthesia is implanted ICV for a long time (icv) and intracardiac venous cannula down at vetanarcol to use known technology.Methylene blue staining when the just absorption that the placement of icv intubate is injected by adversary's postoperative icv carbachol on the same day (100ng/10 μ l) responds (drinking response) and execution confirms.After the operation, rat be placed directly into have in the isolated test cabinet of freely supplying food and water, up to weight recovery to preoperative level (usually in 5-7 days).During this period of time, handle rat every day so that with the experiment same day relevant any stress the minimizing of processing.Testing the same day, and removing food in preceding 1.5 hours in the sampling beginning, and when finishing, give back food.In 6 hours sample period, the specimen of various dose level or physiological saline are in two different time point upper veins or Orally administered.Select time 1100 and 1300, because as the record of previous institute, their reflect the typical peak of GH excretory and paddy period.Human growth hormone's release peptide (5 μ g, PhoenixPharmaceuticals, Inc., Belmont CA) is used as positive control, and only dilutes in physiological saline before use in experiment.For the vital role that evaluation test compound paired pulses GH discharges, in identical time point 1100 and 1300, icv uses the specimen or the physiological saline of low 10 multiple doses.(time: 1000-1600), per 15 minutes from all animal taking-up blood samples (0.35mL) 6 hours sample periods.In order to prove the rapidity of GH response test compound, after the per injection 5 minutes, obtain extra blood sample.All blood samples is centrifugal immediately, and separating plasma and the GH that is used for subsequently-20 ℃ of storages measured.Disturb for fear of Hemodynamics, red corpuscle is suspended in the physiological saline once more, and after taking out next blood sample, be back to animal.All zooscopies all carry out under the rules that animal shows loving care for Watch-dog committee to ratify.
The GH measuring method
(Bethesda, the material that MD) provides are measured blood plasma GH concentration in duplicate by double antibody RIA by NIDDK Hormone Distribution Program in use.The average blood plasma GH value of every group of 5-6 rat is reported according to rat GH reference preparation.All samples with the value that is higher than range of interest are redeterminating after the dilution in 1: 2 to 1: 10 scope.
The result
Intravenously and Orally administered after, exemplary compounds of the present invention provides in Fig. 2 the influence of secretion of growth hormone in cynomolgus monkey.
H. the mouse model of cancer cachexia
The tumour emaciation is considered to the major cause of the treatment restriction of the rapid decline of mortality ratio, quality of life and late tumor patient.Because the antagonistic action of ghrelin receptor is relevant with the generation of the increase of ingestion of food and positive overall energy balance (positive overall energy balance), therefore compound of the present invention is applied to treat this illness.Design following method with research test compounds and ghrelin contrast in as the G361 melanoma model of subcutaneous heterograft growth in BALB/c nu/nu mouse, to the cachectic influence of tumour.(Mori M, Yamaguchi K, people such as Honda S: Cancer Res.1991,51,6656-6659.) other model is known in this area.(Emery，P.W.Nutrition?1999，15，600-603。)
For this method, the mouse of 60 long knurls was divided into 2 batches in back 12 days at random in inoculation, and each 5 groups, every group of 6 animals.When beginning treatment, determine of the mean body weight loss of batch 1 and batches 2 animal with respect to initial mean body weight.Behind the tumor inoculation, began the treatment of batch 1 and batches 2 animal respectively at the 12nd day and the 16th day.Group 1 and group 6 one days 2 times i.v., s.c. or oral acquisition vehicles (according to the mode of administration of test compounds) individually, organize 5 and group 10 then s.c. use rat ghrelin (1mg/kg; One day 2 times, 6 hours at interval) as positive control.Test compounds every day 2 i.v., s.c. or Orally administered of three dosage levels (for example 3,10,30mg/kg), 6 hours at interval, 20-40 days continuously.During the research, reject mouse according to predetermined standard, standard comprises＞15% initial body weight loss and/or gross tumor volume surpass 2000mm 3And/or show serious clinical symptom.
Measuring body reconnects the consumption with food and water.In addition, determine treating in the course of treatment, the blood plasma level of cholesterol, triglyceride level, non-esterified fatty acid and blood sugar is with the influence of further measurement test compounds to the animal general health.
I. to the evaluation of the stripped effectiveness at the bottom of the rat stomach
Use this method, by handling the rat stomach tail band existing or lack in the isolated organ bath (bath) of electrical field stimulation (EFS), the use ghrelin is estimated the effectiveness of compound of the present invention as activator as a reference.
Method
From the stomach of Thirty male rats, be parallel to circular muscle fiber excision tail band (about 0.4x 1cm).Place them in 10ml organize in the bath two at interval the platinum loop electrode of 1cm (Radnoti, ADInstruments, USA) between, and maintain 37 ℃, the described bath of organizing contains with containing 5%CO 2O 2The Krebs solution of bubbling.Be organized in 1.5g rest tension low suspension.Tensile changes with axles (isometrically) such as force transducers to be measured, and with PowerLab 8/30 data collecting system (ADInstruments, USA) record.Allow structural equation 60 minutes, tank liquor changed once in per 15 minutes therebetween.
By using the 0.5ms pulse, the 5Hz frequency realizes EFS under maximum virtual voltage 70V.For 30 minutes initial period, used EFS30 second at interval in 3 minutes.This initial period cuts off by 5 minutes intervals with the tank liquor flushing.Then, start second period that stimulates.Obtaining consistent EFS-inductive contraction back (after three or four times 30 seconds the stimulation), the test compounds of ghrelin, the different concns (for example 0.01-10 μ M) of the non-accumulation application of research, L-NAME in 30 minutes period (300 μ M, in contrast) or their vehicle separately to the influence of response EFS.Measurement is to the response of medicament, and is expressed as the % to three before the response of EFS medicine or four s' mean value.All compound dissolutions are in the distilled water or MeOH of 1mM, as stock solution.
The result
For ghrelin, inotropic EC 50Value is 5nM, for compound 801, and inotropic EC 50Value is 300nM, and for compound 807, inotropic EC 50Value shows the relatively low effectiveness of synthetic Macrocyclic ghrelin agonist in system at the bottom of the isolating rat stomach for 150nM.
J. plasma proteins combination
The pharmacokinetics of medicine and pharmacodynamic properties are that medicine is reversible in conjunction with blood plasma or serum protein to a great extent, such as albumin and α 1The function of-sour glycoprotein.In general, have only unconjugated medicine to can be used for the dispersion or the transportation of cross-cell membrane, and be used for interacting with the pharmacology target.On the other hand, have low plasma proteins bonded medicine and generally have a large amount of distributions and clearance rate fast because have only unconjugated medicine for glomerular filtration and, it is useful that liver is in some cases removed.Therefore, plasma proteins bonded degree can influence effectiveness, distributes and eliminate.Plasma proteins bonded ideal range is in the scope of 87-98% concerning most of medicines.
End user's blood plasma carries out protein binding research.Briefly, use down the test substances 60 minutes that 96 hole microplates hatch different concns at 37 ℃.By equilibrium dialysis separation and combination and unconjugated part, the concentration that wherein remains in bound fraction is not analyzed quantitatively by LC-MS or LC-MS-MS.Medicine with known plasma proteins associated value is used contrast for referencial use such as quinine (～35%), warfarin (～98%) and Naproxen Base (～99.7%).
The result of representative compounds of the present invention sums up in an embodiment.
K. the mensuration that suppresses of Cytochrome P450
Cytochrome P 450 enzymes involves the I stage metabolism of medicine.Most of drug-drug interactions is based on metabolic, and in addition, these interactions generally include the inhibition Cytochrome P450.As if six CYP450 enzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) cause the metabolism of most drug and relevant drug-drug interactions jointly.The bonded mensuration of determining isotype important in the various metabolism of compound pair cell cytochrome p 450 metabolic enzyme of the present invention is commercially available, for example NoAb BioDiscoveries (Mississaugua, ON, Canada) and Absorption Systems (Exton, PA, USA).Similarly, many suitable methods have been described or summary in the literature.(White, R.E.Ann.Rev.Pharmacol.Toxicol.2000,40,133-157; Li, A.P.Drug.Disc.Today 2001,6,357-366; Turpeinen, M.; Korhonen, L.E.Tolonen, people Eur.J.Pharm.Sci.2006 such as A., 29,130-138.)
The critical aspects of experimental technique is as follows:
By the microsome of the insect cell preparation of expressing single people CYP-450 hypotype (
Figure G2008800105877D00721
BD Gentest measures on Becton-Dickinson), particularly:
-CYP hypotype: 1A2,2A6,2B6,2C8,2C9,2C19,2D6,2E1,
3A4
-for common two substrates testing of CYP-3A4, because this enzyme shows complicated inhibition kinetics
2. through fluoroscopic examination, the formation of the fluorescent metabolite behind the microsome is hatched in monitoring with concrete CYP substrate in mensuration.
3. use 3 times of serial dilutions (concentration range 0.0457 μ M to 100 μ M), under eight test concentrations, test compound of the present invention in duplicate sample.
4. for each CYP-450 enzyme, under eight concentration, test concrete inhibitor in duplicate as positive control.
5. by the nonlinear regression analysis of % inhibition, calculate the concentration (IC of the metabolite formation of inhibitor or test compounds inhibition 50% to log concentration (M) curve 50).
The result of representative compounds of the present invention sums up in an embodiment.
L.Caco-2 is infiltrative to be determined
Caco-2 clone derived from human colorectal carcinoma has become the external model of determining that is used to predict the drug absorption of striding people's intestines.(Sun，D.；Yu，L.X.；Hussain，M.A.；Wall，D.A.；Smith，R.L.；Amidon，G.L.Curr.Opin.Drug?Discov.Devel.2004，7，75-85；Bergstrom，C.A.Basic?Clin.Pharmacol.Toxicol.2005，96，156-61；Balimane，P.V.；Han，Y.H.；Chong，S.AAPS?J.2006，8，E1-13；Shah，P.；Jogani，V.；Bagchi，T.，Misra，A.Biotechnol.Prog.2006，22，186-198。) when cultivating on semi-permeable membranes, the Caco-2 cytodifferentiation is to have obviously similar to the small intestine cylindrical epithelium morphology and the epithelium barrier of biochemical height functionalization.Fen Hua cell monolayer can be used for estimating the film transportation character of novel cpd fully.In addition, the apparent permeability coefficient (P that obtains from the transportation research of Caco-2 cell App) shown relevant with people's intestinal absorption appropriateness.
Use the Caco-2 cell to determine that the infiltrative mensuration of compound of the present invention is commercially available, for example NoAb BioDiscoveries (Mississaugua, ON, Canada) and AbsorptionSystems (Exton, PA, USA).
Alternatively, parallel artificial rust perviousness mensuration (PAMPA) can be used for estimating the intestines perviousness.(Avdeef，A.Expert?Opin.Drug.Metab.Toxicol.2005，1，325-42。)
Method
By cell is grown being positioned on two films between (give body and acceptor) chamber, determine to stride the perviousness of Caco-2 cellular layer.Drug candidates is added top (A) face of cellular layer usually to, and measures their appearance at the substrate outside (B) face in incubation time.The perviousness of this direction is represented intestinal absorption.Also can determine perviousness from the substrate outer side of Caco-2 cell to top surface.With the P of the substrate outside to the top AppContrast, the top is to basolateral P AppHigher, indicate carrier mediated transportation.When observing with respect to the top to basolateral P App, the substrate outside is to the P at top AppWhen higher, the transportation of expression P-gp mediation.
Measure in duplicate compound of the present invention at the top outside the substrate outside and the substrate perviousness (10 μ M) on the top-direction.To collect sample from giving body and receptor compartment in beginning (0 minute) with after hatching 60 minutes under 37 ℃, and-70 ℃ of following frozen for storage, up to bioanalysis.The sample that originates from each test compounds of Caco-2 perviousness mensuration is further analyzed by LC-MS-MS.Replicate(determination) [ 3H]-N.F,USP MANNITOL and [ 3H]-perviousness of Proprasylyte is in contrast.
Permeability coefficient (the P of each compound and radiolabeled standard App) use following equation to determine:
P app = dQ dT × 1 / C i × 1 / A
Wherein dQ/dT represents infiltration rate, C iThe starting point concentration in the body chamber (donor compartment) is given in expression, and A represents the surface-area of strainer.Determine C from adding to the mean concns of the multiple sample of obtaining before the body chamber iThe figure that changes along with the time by the accumulation volume that is plotted in the compound of measuring in the receptor compartment (acceptor compartment), and determine that by linear regression analysis the slope of line calculates infiltration rate.Report that the multiple of each compound and standard and average top are to basolateral P AppWith the P of the substrate outside to the top App
The result of representative compounds of the present invention sums up in an embodiment.
M. activation-desensitization feature
The agonist of known g protein coupled receptor can be induced desensitization or tachysynthesis, thereby the restriction medicament acts on the potentiality of acceptor as the therapy that is used for life-time service.(Luttrell，L.M.MethodsMol，Biol.2006，332，3-49；Kenakin，T.Ann.Rev.Pharmacol.Toxicol.2002，42，349-379；Kenakin，T.Nat.Rev.Drug?Discov.2002，1，103-110；Ferguson，S.S.Pharmacol.Rev.2001，53，1-24。) this method uses the HEK293 cell of stably express hGHS-R1a, is used for estimating with respect to the reference agonist receptor activation of compound of the present invention-desensitization feature.
Method
1. ghrelin, GHRP-6 and Ka Mo Rayleigh agonist for referencial use.
2. be written into Ca + 2Behind the indicator Fluo-4-AM, measure the Ca of agonist induction + 2Flux.
3. calculate the negative logarithm (pEC of the agonist concentration of 50% maximal stimulation that causes hGHS-R1a 50).
4. calculate the negative logarithm (PDC of concentration before 50% hatch will be reduced to its control value to the peak response of ghrelin 50).
5. in order to contrast the relative activation-desensitization feature of ghrelin agonist, calculate the pEC of individualized compound 50And pDC 50Value poor, and higher positive number expection has lower desensitization potentiality, and therefore be suitable as the treatment prolonged application.
The result
Compound Δ (activation-desensitization) (pEC 50-pDC 50)
Ghrelin ??0.85
??GHRP-6 ??0.60
Block not Rayleigh ??0.91
??801 ??3.30
??807 ??3.08
??826 ??1.90
100 to 1000 efficiency-timed power differences between receptor activation and the desensitization show compound of the present invention when repeated exposure, should tend to the plain releasing peptide receptor desensitization of induced growth relatively lowly.
4. pharmaceutical composition
Macrocylc compound of the present invention or can be mixed with the pharmaceutical composition of different dosage form according to acceptable salt on its pharmacology of the present invention.In order to prepare pharmaceutical composition of the present invention, one or more compounds (comprising its optical isomer, enantiomorph, diastereomer, racemic modification or stereochemistry mixture) or its pharmacy acceptable salt as activeconstituents closely mix with suitable carriers and additive according to the technology known to the technician of field of pharmaceutical preparations.
Pharmacy acceptable salt refers to the salt form of compound of the present invention, this is in order to allow them as drug use or preparation, and it has kept the biopotency of the free bronsted lowry acids and bases bronsted lowry of particular compound, and its be not biologically or other aspects do not expect.The case description of this salt is in Handbook of Pharmaceutical Salts:Properties, Selection, and Use (drug salts handbook: character, selection and purposes), Wermuth, C.G. and Stahl, P.H. (editor), Wiley-VerlagHelvetica Acta, Z ü rich, 2002[ISBN 3-906390-26-8].The example of this salt comprises the additive salt of an alkali metal salt and free bronsted lowry acids and bases bronsted lowry.The example of pharmacy acceptable salt includes but not limited to vitriol, pyrosulphate, hydrosulfate, sulphite, hydrosulphite, phosphoric acid salt, monohydric phosphate (monohydrogenphosphate), dihydrogen phosphate, metaphosphate, pyrophosphate salt, muriate, bromide, iodide, acetate, propionic salt, caprate, octylate, acrylate, formate, isobutyrate, hexanoate, enanthate, propiolate (propiolate), oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butine-1, the 4-diacid salt, hexin-1, the 6-diacid salt, benzoate, chloro benzoate, tolyl acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, phthalate, xylenesulfonate, phenylacetate, phenpropionate, benzenebutanoic acid salt, Citrate trianion, lactic acid salt, gamma hydroxybutyrate, glycollate, tartrate, mesylate, esilate, propanesulfonic acid salt, tosylate, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt and mandelate.
If the compound of invention is an alkali, desired salt can be by the prepared by any suitable process known to those skilled in the art, described method comprises with mineral acid or with organic acid handles free alkali, mineral acid is such as, but not limited to hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, carbonic acid, sulfuric acid, nitric acid, phosphoric acid and similarly acid, organic acid includes but not limited to formic acid, acetate, propionic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, stearic acid, xitix, oxyacetic acid, Whitfield's ointment, pyranose thuja acid (pyranosidyl acid) (such as glucuronic acid or galacturonic acid), alpha-hydroxy acid (such as citric acid or tartrate), amino acid (such as aspartic acid or L-glutamic acid), aromatic acid (such as phenylformic acid or styracin), sulfonic acid (tosic acid, methylsulfonic acid, ethyl sulfonic acid, the 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, cyclohexyl-thionamic acid) or similarly acid.
If the compound of invention is acid, desired salt can be by prepared by any suitable process known in the art, and described method comprises with inorganic or organic bases handles free acid, alkali such as amine (primary amine, secondary amine or tertiary amine); Basic metal or alkaline earth metal hydroxides; Or similar alkali.The illustrative examples of suitable salt comprises from following deutero-organic salt: amino acid, such as glycine, Methionin and arginine; Ammonia; The primary, the second month in a season and tertiary amine, such as quadrol, N, N '-dibenzyl-ethylenediamin, diethanolamine, choline and PROCAINE HCL, PHARMA GRADE, and cyclic amine are such as piperidines, morpholine and piperazine; And from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium deutero-inorganic salt.
The carrier that is used for this class pharmaceutical composition can adopt different forms according to the mode of administration of expection with additive.Therefore, Orally administered composition can be, for example, solid preparation such as tablet, sugar coated tablet, hard capsule, soft capsule, granula, pulvis and similar formulation, and suitable carriers and additive are starch, sugar, tamanori, thinner, granulating agent, lubricant, disintegrating agent and similar substance.Because they use and higher patient's conformability easily, tablet and capsule are represented the best oral dosage form of many medical conditions.
Similarly, the composition of liquid preparation comprises solution, emulsion, dispersion, suspension, syrup, elixir and similar formulation, and suitable carriers and additive are water, alcohol, oil, ethylene glycol, sanitas, seasonings, tinting material, suspension agent and similar material.The exemplary formulations of parenteral administration comprises activeconstituents and carrier, the acceptable oil of described carrier such as sterilized water or parenteral, comprise polyoxyethylene glycol, polyvinylpyrrolidone, Yelkin TTS, peanut oil or sesame oil, and can comprise other additives of assist in dissolving or preservative activity.Under the situation of solution, it can be lyophilized into pulvis, restores to the original state immediately before use then.For dispersion and suspension, suitable carriers and additive comprise moisture natural gum (aqueous gums), Mierocrystalline cellulose, silicate or oil.
According to the pharmaceutical composition of embodiment of the present invention comprise be suitable for oral, rectum, local, suck (for example passing through aerosol), cheek (for example hypogloeeis), vagina, the part (is skin and mucous membrane surface, comprise airway surface), transdermal administration and parenteral are (for example subcutaneous, intramuscular, intracutaneous, intraarticular, in the pleura, intraperitoneal, in the sheath, in the brain, encephalic, intra-arterial or intravenously) pharmaceutical composition, although under any given situation, only approach will depend on the character and the seriousness of the illness of being treated, and depend on the character of employed particular active agent.
The composition that is used to inject will comprise activeconstituents together with suitable carriers, and described carrier comprises propylene glycol-alcohol-water, isotonic water, the sterilized water (USP), the emulPhor that are used to inject TM-alcohol-water, cremophor-EL TMOr other suitable carriers well known by persons skilled in the art.These carriers can use separately or be used in combination with other conventional solubilizing agent (such as ethanol, propylene glycol) or other medicaments well known by persons skilled in the art.
Under the situation that macrocylc compound of the present invention is used with the form of solution or injection liquid, this compound can use by dissolving or the thinner that is suspended in any routine.Thinner can comprise, for example, and physiological saline, Ringer's solution, D/W, the dextrose aqueous solution, alcohol, fatty acid ester, glycerine, ethylene glycol, derived from plant or zoogenous oil, paraffin and similar thinner.These preparations can prepare according to any ordinary method known to those skilled in the art.
The composition that is used for nasal administration can be formulated as aerosol, drops (drops), pulvis and gel.Aerosol preparations is usually included in the solution or the fine suspension of the activeconstituents in acceptable water solvent on the physiology or the non-aqueous solvent.These preparations are present in the sealed vessel with the sterile form of single dose or multiple doses usually.Sealed vessel can be a tube, or can fill with to use with spraying equipment again.Alternatively, sealed vessel can be single partitioning device, and such as nasal inhaler, pump sprayer or the aerosol dispenser of independent use, it is equipped with the metering valve that is set to transmit the treatment significant quantity, and this equipment is intended to after inclusion uses up fully it be disposed.When formulation comprises aerosol dispenser, it will contain propelling agent, such as pressurized gas (for example air) or comprise organic propelling agent of fluorochlorohydrocarbon or fluorohydrocarbon.
The composition that is suitable for cheek or sublingual administration comprises tablet, lozenge and lozenge, and wherein activeconstituents is with carrier (such as sugar and Sudan Gum-arabic, tragacanth or gelatin and glycerine) preparation.
The composition that is suitable for rectal administration comprises the suppository that contains conventional suppository bases (such as oleum theobromatis).
The composition that is suitable for transdermal administration comprises ointment, gel and paster.
Other compositions well known by persons skilled in the art also can be used for through skin or subcutaneous administration such as plaster.
In addition, preparing this comprising in one or more activeconstituentss and the necessary composition blended of the compositions formulated pharmaceutical composition, can mix acceptable additive on other conventional pharmacology, for example, vehicle, stablizer, sanitas, wetting agent, emulsifying agent, lubricant, sweeting agent, tinting material, seasonings, isotonic agent, buffer reagent, antioxidant and similar additive.As additive, may mention, for example, starch, sucrose, fructose, dextrose, lactose, glucose, N.F,USP MANNITOL, sorbyl alcohol, precipitated chalk, crystalline cellulose, carboxymethyl cellulose, dextrin, gelatin, Sudan Gum-arabic, EDTA, Magnesium Stearate, talcum, Vltra tears, Sodium Pyrosulfite and similar additive.
In some embodiments, composition provides with unit dosage (such as tablet or capsule).
In further embodiment, the invention provides test kit, it comprises one or more containers, and described container comprises pharmaceutical dosage unit, and described pharmaceutical dosage unit contains one or more compounds of the present invention of significant quantity.
The present invention further provides the prodrug that comprises compound described herein.Term " prodrug " be used for meaning under physiological condition or by solvolysis or metabolism be converted into the pharmaceutically compound of activated specific compound." prodrug " can be compound of the present invention, it is by consequently chemically derived, (i) its kept its parent drug compound some, all biological is active or the biological activity that do not keep its parent drug compound, and (ii) its in the curee metabolism to produce the parent drug compound.Prodrug of the present invention can also be " a part prodrug ", wherein this compound is by consequently chemically derived, (i) its kept its parent drug compound some, all biological is active or the biological activity that do not keep its parent drug compound, and (ii) its in the curee metabolism to produce the biologically active derivatives of this compound.Can use and be used for derivative compound so that the known technology of prodrug to be provided.This method can be utilized the hydrolyzable link coupled formation with compound.
The present invention further provides: compound of the present invention can be used to prevent and/or treat following treatment of conditions agent combined administration: metabolism and/or endocrine disorder, gastrointestinal disorder, cardiovascular disorder, obesity and obesity associated conditions, central nervous system disorders, osteopathy, hereditary illness, hyper-proliferative illness and inflammatory conditions.Exemplary medicament comprises analgesic agent (comprising the OPIOIDS analgesic agent), narcotic, anti-mycotic agent, microbiotic, anti-inflammatory agent (comprising non-steroidal anti-inflammatory agent), anthelmintics, antiemetic, antihistaminic agent, hypotensive agent, antipsychotic drug, anti-arthritic, anti-tussive agents, antiviral agent, cardioactive medicine, purgatives, chemotherapeutics is (such as DNA interaction medicament (DNA-interactive agents), metabolic antagonist, tubulin interaction medicament (tubulin-interactive agents), hormone agents, and such as the medicament of asparaginase or hydroxyurea), adrenocortical hormone (steroid), thymoleptic, inhibitor, diuretic(s), soporific, mineral substance, nutritional supplement, Parasympathomimetic, hormone is (such as corticotropin releasing hormone, thyroliberin, growth hormone releasing hormone, tethelin, thyrotropic hormone (thyrptropin) releasing hormone and thyrotropic hormone), tranquilizer, sulfonamide, stimulant, sympathomimetic, tranquillizer, vasoconstrictor, vasodilator, VITAMIN and xanthine derivative.
The curee who is suitable for the treatment according to the present invention includes but not limited to bird and mammalian subject, and preferred mammal.Mammals of the present invention includes but not limited to dog, cat, ox, goat, horse, sheep, pig, rodents (for example rat and mouse), rabbit, primates, people and similar Mammals and intrauterine Mammals.Any mammalian subject that need treat according to the present invention all is suitable.Preferred people curee.Two sexes and any etap, the people curee of (be newborn infant, baby, teenager, teenager, grow up) can treat according to the present invention.
Exemplary bird according to the present invention comprises bird (birds in ovo) in chicken, duck, turkey, goose, quail, pheasant, ratite bird (for example ostrich) and domestic bird (for example parrot and canary bird) and the ovum.
The present invention mainly pays close attention to treatment people curee, but the present invention also can carry out on animal subject, described animal subject is especially for animal doctor's purpose and the mammalian subject that is used for drug screening and drug development purpose, such as mouse, rat, dog, cat, domestic animal and horse.
In the treatment of the illness of treatment Mammals (being the human or animal) is used, and be effectively, can use compound of the present invention or its suitable pharmaceutical compositions of significant quantity for the conditioning agent (such as agonist) of this illness ghrelin receptor.Because the degree of the activity of compound and curative effect changes, so the actual dose of being used will be determined according to factor such as the age of generally having approved, curee's illness, administration route and curee's body weight.Dosage can be from about 0.1mg/kg to about 100mg/kg, Orally administered 1-4 time of every day.In addition, can pass through the injection administered compound by the about 0.01-20mg/kg of every dosage, and use 1-4 time every day.Treatment is several weeks, several months or longer continuously.For particular case, optimal dose fixes in those skilled in the art's the limit of power really.
5. using method
Compound of the present invention can be used for prevention and treats a series of medical science disease favours, include but not limited to metabolism and/or endocrine disorder, gastrointestinal disorder, cardiovascular disorder, obesity and obesity associated conditions, central nervous system disorders, osteopathy, hereditary illness, hyper-proliferative illness, inflammatory conditions and combination thereof, wherein illness can be caused by a plurality of potential diseases.In specific embodiment, this disease or illness are irritable bowel syndrome (IBS), non-ucler dyspepsia, crohn, gastroesophageal reflux disease, constipation, ulcerative colitis, pancreatitis, congenital hypertrophic pyloric stenosis, carcinoid syndrome, malabsorption syndrome, diarrhoea, diabetes (comprising diabetes (diabetes mellitus) (type ii diabetes)), obesity, atrophic colitis, gastritis, gastric retention, the stomach and intestine dumping syndrome, gastrointestinal anastomosis postoperative syndrome (postgastroenterectomy syndrome), celiac disease, eating disorder or obesity.In other embodiment, this disease or illness are congestive heart failure, ischemic heart disease or morbus cardiacus.In other other embodiment, this disease or illness are osteoporosis and/or fragility, congestive heart failure, the fracture of quickening is recovered, metabolism syndrome, the protein catabolism response that weakens, emaciation, protein loss, poor wound healing or bad risk, the risk that burn rehabilitation is bad or bad, the risk that surgery recovery is bad or bad, the risk of muscular strength damage or damage, the risk of sport injury or damage, the risk that skin thickness changes or changes, the risk of metabolic balance damage or damage, or the risk of damage of kidney homeostasis or damage.In other embodiment, this disease or illness comprise the promotion neonatal development, stimulate people's tethelin to discharge, keep people's muscular strength and function, reverse or prevent people's fragility, the katabolism side effect of prevention glucocorticosteroid, the treatment osteoporosis, stimulate and increase muscle quality and muscular strength, stimulating immune system, accelerating wound healing, quickening fracture recovers, treat renal failure or cause slow growing functional defect, treat of short and small stature, treatment of obesity and growth retardation, quicken fire victim's recovery and reduce its hospital stays, the treatment intrauterine growth retardation, the treatment skeleton development is bad, the treatment hypercortisolism, the treatment hypercortisolism, induce the pulsed growth hormone to discharge, the tethelin of displacement stressed patients (stressed patients), the treatment osteochondrodysplasia, the treatment Noonan syndrome, treatment schizophrenia, the treatment dysthymia disorders, the treatment alzheimer's disease, the treatment vomiting, the treatment memory loss, treatment reproduction illness, the wound healing that treatment postpones, treatment psychosocial deprivation, the treatment pulmonary dysfunction, the treatment respirator relies on; The protein catabolism response weakens, emaciation that weakens and protein loss, the treatment hyperinsulinemia, the assisting therapy of induced ovulation, stimulate thymus development, the decline of prevention thymus function, the treatment immunosuppressed patient, improve the muscle movability, keep skin thickness, metabolic balance, kidney homeostasis, stimulating osteoblast, stimulate bone remodeling, stimulate cartilage-derived growth, stimulate the immunity system of companion animals, the aging illness of treatment companion animals, the growth of domestic animal, and/or the wool growth that stimulates sheep.Other embodiment provides the method for treatment inflammatory conditions, the gastric injury that comprises sepsis, ischemia reperfusion injury, pancreas and liver injury, sepsis and septic shock in the ulcerative colitis, inflammatory bowel, crohn, pancreatitis, rheumatoid arthritis, osteoarthritis, asthma, vasculitis, psoriasis, rhinallergosis, peptic ulcer disease, postoperative abdomen, caused by some drugs, the gastric injury of stress-induced, by the microbial gastric injury of helicobacter pylorus, inflammatory pain, chronic nephropathy and enteritis.
According to a further aspect of the present invention, provide the following illness of treatment in the humans and animals patient of the hardship that suffers following illness: postoperative ileus, emaciation (expendable syndrome) is (such as by cancer, AIDS, the emaciation that heart trouble and ephrosis cause), gastroparesis (such as the gastroparesis that causes by I type or type ii diabetes), other gastrointestinal disorders, growth hormone deficiency, the method of the illness that bone loss is relevant with other ages, this method comprises at least one member who is selected from compound disclosed herein who uses significant quantity to described patient, and described compound has the ability of regulating ghrelin receptor.The other diseases and the illness of being treated by compound disclosed herein comprise short bowel syndrome, stomach and intestine dumping syndrome, gastrointestinal anastomosis postoperative syndrome, celiac disease and hyper-proliferative illness, such as tumour, cancer and tumprigenicity illness and premalignant and non-tumprigenicity or non-pernicious hyper-proliferative illness.Especially, can be by the tumour of the present invention's treatment, cancer and tumor tissues include but not limited to malignant disorders, such as breast cancer, osteosarcoma, angiosarcoma, fibrosarcoma and other sarcomas, leukemia, lymphoma, the hole knurl, ovarian cancer, carcinoma of ureter, bladder cancer, prostate cancer and other urogenital cancers, colorectal carcinoma, the esophageal carcinoma and cancer of the stomach and other gastric and intestinal cancers, lung cancer, myelomatosis, carcinoma of the pancreas, liver cancer, kidney, the internal secretion cancer, skin carcinoma and pernicious or benign cerebral tumor or maincenter and peripheral nerve (CNS) system tumor comprise neurospongioma and neuroblastoma.
In specific embodiment, macrocylc compound of the present invention can be used for treating postoperative ileus.In other embodiment, compound of the present invention can be used for treating gastroparesis.In other other embodiment, compound of the present invention can be used for treating diabetic gastroparesis.In another embodiment, compound of the present invention can be used for treating OPIOIDS inductive intestinal dysfunction.In further embodiment, compound of the present invention can be used for treating chronic intestinal pseudo-obstruction.
In the specific embodiment of the present invention, compound of the present invention can be used for treating postoperative ileus, gastroparesis, OPIOIDS inductive intestinal dysfunction, chronic intestinal pseudo-obstruction, acute colon Pseudo-Obstruction (Ogilvie syndrome), short bowel syndrome, vomiting, constipation is main irritable bowel syndrome (IBS), chronic constipation, the maldigestion syndrome that cancer is relevant, the stomach emptying that postpones, the gastrointestinal dysfunction among the Parkinson's disease patient or the stomach emptying of delay, the gastrointestinal dysfunction in the steirert-Batten-Gibb syndrome or the stomach emptying of delay, the gastrointestinal dysfunction among the scleroderma patient or the stomach emptying of delay, gastroesophageal reflux disease (GERD), stomach ulcer or crohn.
The present invention further provides the method for the gastrointestinal disorder of treatment horse or dog, it comprises the conditioning agent of the structure with formula I of administering therapeutic significant quantity.In some embodiments, gastrointestinal disorder is intestinal obstruction or angina.
As used herein, " treatment " must not mean the hint healing or eliminate illness or the symptom relevant with illness fully.
Compound of the present invention can be further used for preparing the medicine that is used for the treatment of a series of medical disorder, and described illness includes but not limited to metabolism and/or endocrine disorder, gastrointestinal disorder, cardiovascular disorder, central nervous system disorders, obesity and obesity associated conditions, hereditary illness, osteopathy, hyper-proliferative illness and inflammatory conditions.
With reference to following embodiment further embodiment of the present invention is described.Should be understood that these embodiment are in order to explain the purpose of embodiment of the present invention, and do not limit the scope of the invention.
Embodiment
Embodiment 1
In conjunction with active
Following table shows that representative compounds of the present invention is active to the combination of human growth hormone's releasing peptide receptor.
Compound number ??K i(nM) a Compound number ??K i(nM) a
??801 ??A ??1008 ??C
??802 ??C ??1009 ??A
??803 ??C ??1010 ??B
??807 ??B ??1011 ??B
??808 ??C ??1014 ??D
??809 ??C ??1015 ??D
??810 ??C ??1016 ??C
??813 ??B ??1017a ??C
??816 ??B ??1017b ??D
??818 ??B ??1018 ??C
??819 ??B ??1019a ??D
??820 ??C ??1019b ??E
??822 ??C ??1020a ??C
??825 ??B ??1020b ??C
??826 ??C ??1021 ??E
??828 ??A ??1022 ??D
??829 ??A ??1023 ??C
??831 ??A ??1024 ??C
??832 ??A ??1025 ??D
??833 ??B ??1026 ??C
??851 ??C ??1027 ??C
??853 ??C ??1028 ??C
??854 ??C ??1029 ??B
??855 ??C ??1030 ??C
??856 ??D ??1031 ??C
??857 ??D ??1032 ??D
??858 ??D ??1033 ??C
??859 ??D ??1034 ??C
??860 ??B ??1035 ??C
??862 ??B ??1036 ??E
??863 ??C ??1038 ??C
??864 ??B ??1039 ??C
??865 ??C ??1040 ??C
??866 ??C ??1041 ??C
??867 ??C ??1042 ??C
??869 ??C ??1043 ??C
??870 ??D ??1044 ??D
??871 ??D ??1045 ??C
??872 ??B ??1046 ??C
??873 ??C ??1047 ??C
??874 ??C ??1048 ??E
??876 ??C ??1049 ??C
??877 ??C ??1050 ??E
??878 ??C ??1052 ??A
??923 ??C ??1053 ??C
??934a ??C ??1058 ??C
??934b ??E ??1061 ??C
??935 ??C ??1062 ??B
??936 ??C ??1065 ??C
??937 ??D ??1066 ??C
??938 ??C ??1068 ??C
??939 ??C ??1069 ??C
??944 ??D ??1071 ??D
??945 ??D ??1072 ??D
??946 ??B ??1074 ??C
??947 ??B ??1075 ??C
??950 ??D ??1076 ??C
??951 ??D ??1078 ??C
??954 ??D ??1079 ??C
??965 ??D ??1080 ??C
??966 ??D ??1081 ??E
??968 ??C ??1082 ??D
??969a ??C ??1083 ??C
??969b ??C ??1084 ??C
??972 ??C ??1085a ??C
??973a ??C ??1085b ??C
??973b ??E ??1086 ??C
??974 ??C ??1087a ??D
??975 ??C ??1087b ??C
??976 ??C ??1088 ??D
??977 ??D ??1089a ??C
??978 ??C ??1089b ??D
??979 ??C ??1090 ??D
??981 ??B ??1098a ??D
??982 ??A ??1098b ??C
??986 ??E ??1099 ??A
??987 ??D ??1100 ??B
??988 ??C ??1101 ??D
??989 ??C ??1103 ??E
??991 ??C ??1104 ??C
??992 ??C ??1105 ??A
??993 ??C ??1106 ??C
??994 ??C ??1107 ??C
??995 ??C ??1108 ??A
??996a ??B ??1109 ??B
??996b ??D ??1110 ??C
??997 ??D ??1111 ??C
??998 ??C ??1112 ??A
??999a ??E ??1113 ??A
??999b ??D ??1114 ??A
??1000 ??D ??1115 ??D
??1003 ??C ??1116 ??C
??1005 ??C ??1118 ??B
??1006 ??D ??1119 ??C
??1007 ??C
aUse standard method A to determine in conjunction with active K iValue is expressed as follows: A≤1nM, B≤10nM, C≤100nM, D≤500nM, E＞500nM.
Embodiment 2
Functionally active
Following table shows the functionally active of representative compounds of the present invention to human growth hormone's releasing peptide receptor.
Compound ??EC 50(nM)
??807 ??A
??877 ??A
??968 ??C
??969a ??C
??969b ??C
??973a ??C
??973b ??C
??975 ??D
??976 ??C
??982 ??A
??802 ??B
??1009 ??A
??1018 ??C
??1033 ??B
??1043 ??B
??1058 ??B
??1061 ??B
??1062 ??A
bUse standard method B to determine functionally active, EC 50Value is expressed as follows: A≤50nM, B≤100nM, C≤400nM, D＞400nM.
Embodiment 3
Oral pharmaceutical kinetics
Following table is presented at the oral administration biaavailability of representative compounds of the present invention in the rat and eliminates the data of transformation period.Behind the compound of Orally administered 8mg/kg dosage, determine parameter by HPLC-MS, except compound 822, it uses 2mg/kg dosage.
Compound Eliminate transformation period (t 1/2, rat, minute) Oral administration biaavailability (rat, %F)
??801 ??42 ??4
??802 ??160 ??26
??803 ??151 ??9
??807 ??197 ??23
??808 ??238 ??18
??810 ??116 ??15
??813 ??31 ??4
??819 ??116 ??12
??820 ??137 ??18
??822 ??65 ??51
??825 ??101 ??37
??826 ??77 ??29
??829 ??45 ??8
??831 ??120 ??15
??854 ??223 ??22
??862 ??77 ??22
??877 ??255 ??15
??935 ??42 ??11
??968 ??103 ??26
??979 ??34 ??11
??989 ??138 ??7
??999 ??122 ??9
??1011 ??268 ??22
??1027 ??46 ??6
??1061 ??23 ??4
??1069 ??128 ??32
In addition, representative compounds 802,807,810,819,822,825,831,854,877,968,1011 and 1069 plasma concentration and time relation curve provide in Fig. 3-8.
Embodiment 4
Interaction characteristic with the cytochrome P 450 enzymes hypotype
Representative compounds of the present invention is to the inhibition of CYP P450 isozyme.
Figure G2008800105877D00891
Embodiment 5
Perviousness is measured
Following table shows the Caco-2 perviousness determination data of representative compounds of the present invention.
Compound A is to the P of B appCm/ x10 second -6 B is to the P of A appCm/ x10 second -6 B is to A/A to B
??801 ??163 ??110 ??0.672
??803 ??12.1 ??67.3 ??5.59
??811 ??125 ??198 ??1.59
??825 ??113 ??123 ??1.08
??826 ??11.2 ??46.9 ??4.18
Embodiment 6
Protein binding
Following table is presented at the protein binding data of representative compounds of the present invention in people and the rat plasma.
Compound Test concentrations (μ g/mL) Human plasma protein fraction is in conjunction with (%) Rat plasma protein binding (%)
??801 ??3 ??88.4 ??nd
??802 ??1 ??93.4 ??99.8
??803 ??1 ??97.8 ??99.1
??807 ??5 ??99.3 ??84.0
??808 ??5 ??99.9 ??89.2
??809 ??3 ??88.4 ??92.8
??810 ??3 ??78.9 ??nd
??819 ??3 ??95.2 ??98.2
??820 ??3 ??99.0 ??98.8
??822 ??3 ??93.0 ??99.1
??825 ??1 ??83 ??96.6
??825 ??5 ??70 ??73
??826 ??3 ??94.3 ??97.2
??828 ??3 ??76.8 ??nd
??829 ??3 ??91.6 ??nd
??832 ??3 ??88.9 ??97.3
??833 ??3 ??77.4 ??94.0
??1118 ??3 ??92.8 ??95.5
Nd=does not determine
Embodiment 7
The stomach emptying model
The effect of the representative compounds of the present invention in the rat stomach emptying model of describing in standard method E provides in following table.Carrying out repeatedly showing each result's mean value under the situation of experiment.
The per-cent of Orally administered back stomach emptying increases
Figure G2008800105877D00911
Figure G2008800105877D00921
-expression is not determined
Shown in embodiment 3, some in these compounds demonstrate the long relatively transformation period, can expect that they can be extended the effect of stomach emptying.In fact, compound 807 has confirmed this point, and wherein gastric emptying rate keep to increase (18-23%) and can reach after the administration 24 hours.
Should also be noted that the effectiveness of the promotion stomach emptying of compound 801, although its oral administration biaavailability only is 4% (embodiment 3).This shows that compound of the present invention and some other material have the part and actuate activity in the GI system, and restriction systemic exposure (systemic exposure).Side effect reduced when this character can cause them to use as medicament.
Embodiment 8
Postoperative ileus
The effect of representative compounds in treatment rat postoperative ileus.
Method
From
Figure G2008800105877D00922
Deng people (1998), the model that Ann Surg 228:652-63 revises.
2. (male, Sprague-Dawley is 250-300g) to be suitable for the test substances administration jugular vein conduit to be implanted rat.
3. make rat fasting O/N, use isoflurane anesthesia, and stand abdominal operation.
4. behind the abdominal incision, take out small intestine caecum and large intestine in 15 minutes time, and preserve moisture with salt solution.
5. carry out " runnings of intestines ", a kind of clinical relevant treatment of intestines is characterized by and at first pushes the small intestine upper end, and continues this operation and pass through large intestine downwards.
6. after any effect of isoflurane anesthesia disappears, allow rat to begin 15 minutes recovery.
Rat with the suitable dose level (for example 30,100 or 300g/kg, i.v., vehicle N=6/gp) or test compounds administration gavage in the stomach subsequently 99mTc methylcellulose gum (2%) meal.
8.15 after minute, make rat euthanasia, and separate the part of the continuous 10cm of stomach and intestines.Measure radioactivity in each separate tissue thing ( 99mTc) as the method for measuring the canteen transportation.
Embodiment 9
The stomach emptying that OPIOIDS postpones
In the stomach emptying model that OPIOIDS postpones, representative compounds is to the influence of stomach emptying and stomach and intestine transportation.
The known OPIOIDS analgesic agent such as morphine postpones the stomach and intestine transportation, and this is the main side effect of this class medicine.This syndromic clinical term is OPIOIDS intestinal dysfunction (OBD).Importantly, the postoperative ileus that stands of the patient who recovers from abdominal operation is via the OPIOIDS of the following treatment that is used for post-operative pain and further increase the weight of.The purpose of this program is to determine whether compound of the present invention may have treatment and render a service in treatment OBD.
Method
1. (male, Sprague-Dawley is 250-300g) to be suitable for the test substances administration jugular vein conduit to be implanted rat.
2. use morphine (3mg/kg s.c.) to the rat of overnight fast.
3.30 after minute, rat gavages in the stomach subsequently with the vehicle or the test compounds administration of suitable dose level (for example 300 or 1000 μ g/kg, i.v., n=4/gp to 6/gp) 99mTc methylcellulose gum (2%) meal.
4.15 after minute, make rat euthanasia, and separate the part of the continuous 10cm of stomach and intestines.Measure radioactivity in each separate tissue thing ( 99mTc) as the method for measuring the canteen transportation.
Embodiment 10
The gastroparesis animal model
Known high calorie meal hinders stomach emptying.Recently, this experience is by Megens, and people such as A.A. (not publishing) utilize the rat model of the stomach emptying that is used to postpone with development, and the stomach emptying of described delay is as standing in gastroparesis.
Material
1.Wistar rat is male, 200-250g
2. chocolate test meal: 2mL Clinutren
Figure G2008800105877D00941
(1.0kcal/mL, Nestle SA, VeveySwitzerland)
Method
Test meal is supplied with the curee by oral gavage at place, time=0.After 60 minutes, put to death the curee, excise stomach, and inclusion is weighed.
Place, time=0 is with three dosage level (0.08mg/kg; 0.30-0.31mg/kg; 1.25mg/kg) intravenously uses the aqueous solution or the normal saline solution of test compounds.In case of necessity, add cyclodextrin (CD) with the solubilising material.Time=-30 minutes the time, use the test compounds of using the subcutaneous injection check.Every group of test four to five (4-5) rat, except under the situation of cyclodextrin contrast, ten (10) rats are formed one group in this case.
The result is reported as with respect to the per-cent of injection solvent stomach weight in contrast only, thereby explains the stomach emptying ability of compound of the present invention.
Embodiment 11
Synthesizing of tethers
The standard procedure of A. synthesizing tethers T85
Figure G2008800105877D00951
From 2, (85-1,20g 154mmol) begin to make up tethers Boc-T85 to the 3-difluorophenol, 5 step total recoverys 21%.
TLC:R f: 0.13 (25/75AcOEt/ hexane), detect: UV, triketohydrindene hydrate
1H?NMR(CDCl 3)：6.84(m，2H)，4.19(m，2H)，3.97(m，2H)，3.08(m，2H)，2.95(m，2H)，2.16(s，1H)，1.74(m，2H)，1.44(m，9H)
LC-MS (Grad A4) t R: 6.31 minutes
The standard procedure of B. synthesizing tethers T86
Figure G2008800105877D00952
(302mmol) beginning uses 5 step processes to prepare Boc-T86 for 86-1,33.8g, shows yield 26% (the parent material correction through reclaiming in the step 3) from the 2-fluorophenol.
TLC:R f: 0.33 (50/50AcOEt/ hexane), detect: UV, triketohydrindene hydrate
1H?NMR(CDCl 3)：6.94(m，2H)，5.09(m，1H)，4.15(m，2H)，3.94(m，2H)，3.08(m，2H)，2.70(m，2H)，1.78(m，1H)，1.61(m，2H)，1.44(s，9H)
LC-MS (Grad A4) t R: 6.81 minutes
The standard procedure of C. synthesizing tethers T87
Figure G2008800105877D00961
Use the reaction sequence that shows, from 3-fluoro-2-iodoanisole (87-2,23.4g, 92.7mmol, Grunewald, people J.Med.Chem.1986 such as G.L., 29,1972-1982.) synthetic Boc-T87, total recovery 65%.
TLC, R f=0.3 (AcOEt/ hexane, 1/1)
The standard procedure of D. synthesizing tethers T100
Figure G2008800105877D00971
Step T100-13-bromo-2-hydroxyl-phenyl aldehyde 100-1: under the room temperature, with MgCl 2(2.85g, 30mmol) and triethylamine (10.45mL, 75mmol) join stirring the 2-bromophenol in the 100mL anhydrous acetonitrile (100-0,3.5g, 20mmol) and paraformaldehyde (8.1g is 270mmol) in the suspension.This reaction system of vigorous stirring, backflow is spent the night.Mixture is cooled to room temperature, adds the 5%HCl of 30mL then, and use Et 2The O extraction product is to obtain the 100-1 of 4g (95%).
Step T100-22-bromo-6-vinylphenol 2: under the room temperature, will (4.1g 0.03mol) joins CH at the tBuOK among the THF (50mL) in 5 minutes 3PPh 3(72g is in stirred solution 0.033mol) for Br.Mixture is cooled to-78 ℃, and in 15 minutes, drip 100-1 (3g, 0.015mol).Under the room temperature, reaction mixture was stirred 24 hours.After this time, remove under the vacuum and desolvate, and, use Et by flash column chromatography 2O as elutriant purifying residue to obtain colorless oil 100-2 (2.2g, 75%).
Step T100-3Toluene-4-sulfonic acid 2-(2-bromo-6-vinyl-phenoxy group)-Ding-3-alkene ester 3.Under the room temperature, with the diethylazodicarboxylate (3.5mL, 18mmol) slowly join 110-2 (2.5g, 12mmol), Ph 3(4.6g, 18mmol) (100-A, 4.3g is in 150mL THF solution 18mmol) with toluene-4-sulfonic acid 2-hydroxyl-Ding-3-alkene ester for P.Mixture at room temperature stirred 6 hours, showed to react up to TLC and finished.Under high vacuum, remove and desolvate, and pass through flash column chromatography purifying residue to obtain light brown liquid 100-3 (4.6g, 68%).
Step T100-4Toluene-4-sulfonic acid 8-bromo-2H-chromene-2-base methyl esters 4.Be used in s-generation Grubbs catalyzer (0.02%) among the 50mL DCM handle 100-3 (3.4g, 8mmo1).Mixture at room temperature stirred 6 hours, up to finishing according to the TLC analytical reaction.Under high vacuum, remove and desolvate, and pass through flash column chromatography purifying residue to obtain light brown liquid 100-4 (2.15g, 70%).
Step T100-5Acetic acid 8-bromo-2H-chromene-2-base methyl esters 5.Under the argon gas, (2.09g, (1.43g is in dry DMF 23mmol) (50mL) solution 10.9mmol) to join 100-4 with cesium acetate.Solution was stirred 12 hours down at 50 ℃.After this time, under high vacuum, remove and desolvate, and pass through flash column chromatography purifying residue to obtain light brown liquid 100-5 (0.7g, 70%).
Step T100-6(8-bromo-2H-chromene-2-yl)-methyl alcohol 6.Under the argon gas, the sodium Metal 99.5 of catalytic amount is joined 100-5, and (5.5g is in anhydrous MeOH (150mL) solution 23mmol).Solution at room temperature stirred 30 minutes.After this time, add Amberlite IRA-120 (H +) resin, and with mixture vigorous stirring 10 minutes.By removing by filter resin, and evaporating solvent.Reclaim colorless oil pure compound 100-6 (4.5g, 90%).
Step T100-7[3-(2-methylol-2H-chromene-8-yl)-Propargyl]-carboxylamine 3,5-dimethoxy benzyl ester 7.(4.5g, 18mmol) (100-B, 15.2g 55.8mmol) are dissolved in dioxane (150mL) and Diisopropylamine (27mL), and make the reaction mixture degassing by bubbling argon gas in solution with the Ddz-propargylamine with 100-6.Add Pd Cl 2(PhCN) 2The hexane solution of (430mg, 1.11mmol, 0.06 equivalent), CuI (220mg, 1.11mmol, 0.06 equivalent) and 10% tributylphosphine (4.4mL, 2.23mmol), and with mixture heating up to 70 ℃, and stir and spend the night.Under high vacuum, remove and desolvate, and pass through flash column chromatography purifying residue to obtain light brown liquid 100-7 (3.2g, 80%).
Step T100-8[3-(2-methylol-chroman-8-yl)-propyl group]-carboxylamine 3,5-dimethoxy benzyl ester 8.(4.5g 0.2mol) is dissolved in EtOH (150mL), and with nitrogen purging solution 10 minutes with 100-7.Add PtO then 2(10mol% 450mg), and packs mixture into and (fills hydrogen simply under 60psi with hydrogen flushing, and under vacuum, discharge, and then fill, repeat this filling-releases-filling and circulate three times) the Parr device in, and at room temperature under 60psi, spend the night with hydrogen reaction.Reaction mixture is passed through
Figure G2008800105877D00981
Pad filters (using the washed with methanol residue), and concentrated filtrate to be obtaining in fact pure (according to NMR), but coloured Ddz-T100 sample, quantitative yield.Can realize further purifying by making this material stand flash chromatography.It should be noted that product and parent material have identical R f, therefore need NMR to distinguish them.
1H?NMR(300MHz，CDCl 3)：δ6.82-6.98(m，2H)；6.80-6.75(m，1H)；6.53(s，2H)；6.35(t，1H，2Hz)；5.23(b，1H)；4.08(m，1H)；3.90-3.68(m，8H)；3.20-2.97(m，2H)；2.95-53(m，4H)；2.0-1.63(m，10H)。
13C?NMR(75.5MHz，CDCl 3)：δ160.85；155.56；152.55；149.56；128.13；127.77；120.28；103.22；98.43；80.72；76.80；65.76；55.46；40.23；30.45；29.34；29.22；27.10；24.97；23.94。
E. the standard procedure of synthetic tethers T100a and T100b
By 3-bromo-2-hydroxyl-phenyl aldehyde (100-2, people Acta.Chemica Scand.1999 such as Hofslokken, 53,258) and toluene-4-sulfonic acid 2-hydroxyl-Ding-3-alkene ester (100-4, people Eur.J.Org.Chem.1999 such as Buono, 1671), use crucial closed loop disproportionation step (Grubbs, R.J.Org.Chem.1998,63,864-866; Gross, J.Tetrahedron Letters, 2003,44,8563-8565; Hoveyda, A.J.Am.Chem.Soc.1998,120,2343-2351) carry out the structure of single steric isomer, as being explained by (R)-isomer Boc-T100a.
1H?NMR(300MHz，DMSO-d 6)：δ1.16(s，9H)，1.5-1.8(m，3H)，1.9-2.1(m，1H)，2.4-2.6(m，2H)，2.6-3.0(m，4H)，3.6(tdd，2H，29.7，11.3，5.6Hz)，3.9-4.1(m，1H)，4.8(t，1H，J＝5.7Hz)，6.8-6.9(m，1H)，6.9-7.0(m，1H)，6.8-6.9(m，2H)
13C?NMR(75MHz，DMSO-d 6)：δ23.6，23.8，26.5，28.2，29.6，63.5，76.2，77.2，119.2，121.5，127.1，127.2，128.8，152.1，155.5。
Can similarly synthesize (S)-isomer T100b.
Optional synthetic schemes shown in also can using, it relies on the enzyme process splitting step to provide Cbz-T100a, total recovery 15-20%.
Figure G2008800105877D01001
The standard procedure of F. synthesizing chain T101
Figure G2008800105877D01011
Step T101-1: synthetic aldehyde 101-1 (Meyer, S.D. with S.L.Schreiber J.Org.Chem1994,59,7549-7552): with Dai Si-Martin's oxygenant (Dess-Martin periodinane) (100g, 236mmol, 1.4 equivalent) join in DCM (1L) solution of Boc-aminopropanol (alaninol) (29.5g, 168mmol, 1.0 equivalents).IBX and pyr-SO 3Can be used for oxidation alternatively.Under vigorous stirring, in 0.5 hour, add H with dropping funnel 2O (4.25mL, 1.4 equivalents).Add Et 2O, and solution is filtered, and concentrates by rotatory evaporator then.Residue is dissolved in Et 2O, and use saturated NaHCO in order 3: 10% Sulfothiorine (1: 1), water, salt solution come washing soln.Sometimes, need extra washing first mixture to remove the acetic acid that forms by DMP reagent.The water Et that merges 2O strips once, and the organic phase MgSO that merges 4Dry, filtration and concentrated to obtain 29g (100%) white solid 101-1 by rotatory evaporator, it uses toluene (3 *) azeotropic leniently.This material uses after preparation usually immediately.
TLC:R f=0.3 (hexane/EtOAc, 1/4)
1H?NMR(CDCl 3，300MHz)：δ9.56(s，1H)，5.07(br?s，1H)4.29-4.17(m，1H)，1.45(s，9H)，1.34(d，3H，J＝7.4Hz)。
Step T101-2: under synthetic dibromide 101-2:0 ℃, with PPh 3The activation that (83.9g, 320mmol, 2.0 equivalents) join in DCM (1L) [is used 0.5N HCl (3 *), H 2O (3 *), MeOH (3 *), Et 2O (3 *) washing, and dry under vacuum pump) Zn powder (20.9g, 320mmol, 2.0 equivalents) and CBr 4In (106g, 320mmol, 2.0 equivalents), described PPh 3Divide three parts in 5 minutes, to add with the control thermopositive reaction.Solution at room temperature stirred 24 hours, and during this period of time, color changes pink colour into from yellow.The 101-1 (27.7g, 160mmol, 1.0 equivalents) that has just prepared is joined among the DCM (100mL).In after this 24 hours, solution changes intense violet color into.By the rotatory evaporator concentrated solution, go up purifying to obtain the white solid 101-2 of 25.5g (48%) by flash column chromatography at silica gel (hexane/EtOAc, 10/1) then.
TLC:R f=0.67 (EtOAc/ hexane, 3/7)
1H?NMR(CDCl 3，300MHz)：δ6.34(d，1H，J＝8.2Hz)，4.53(brs，1H)，4.341-4.27(m，1H)，1.45(s，9H)，1.24(d，3H，J＝6.8Hz)。
Step T101-3: under synthetic alkynes 101-3:-78 ℃, drip hexane (2.0M, 116mL, 232.5mmol, the 3.0 equivalents) solution of the n-BuLi of firm titration to anhydrous THF (1.2L) solution of 101-2 (25.5g, 77.5mmol, 1.0 equivalents).Solution stirred 1.0 hours down at-78 ℃.Add 0.01N NaOH solution (300mL) then, and with mixture heating up to room temperature.Water Et 2O (2 * 300mL) extractions.(MgSO is used in 2 * 300mL) washings to the organic phase that merges with salt solution 4Drying concentrates by rotatory evaporator, goes up purifying to obtain 11.1g (85%) white solid 101-3 by flash column chromatography at silica gel (hexane/EtOAc, 4/1) then.
TLC:R f=0.57 (Et 2The O/ hexane, 2/3)
1H?NMR(CDCl 3，300MHz)：δ4.68(br?s，1H)，4.55-4.41(m，1H)，2.24(d，1H，J＝2.3Hz)，1.45(s，9H)，1.40(d，3H，J＝6.9Hz)。
Step T101-4: synthetic alkynes 101-4: to 101-3 (10.0g, 62.1mmol, 1.0 equivalents) and iodo-alcohol [101-A, 22.5g, 80.7mmol, 1.3 equivalents are according to before to T33 (WO2004/111077; WO 2005/012331; WO 2006/009674) description preparation] CH 3The solution of CN (460mL) is used argon gas bubbling 20 minutes.Add firm distillatory Et 3N is (at CaH 2Last backflow 4 hours, distillation then, 31mL, 224mmol, 3.6 equivalents), and with argon gas bubbling 10 minutes.The CuI (355mg, 1.9mmol, 0.03 equivalent) and the PdCl that add recrystallization then 2(PPh 3) 2(1.33g, 1.9mmol, 0.03 equivalent).Under the room temperature, reaction system stirs under argon atmospher spends the night, and monitors with TCL.Remove volatile matter by rotatory evaporator, and go up the purifying residue to obtain the orange solids 101-4 of 18.6g (94%) at silica gel (DCM/EtOAc, 4/1) by flash column chromatography.
TLC:R f=0.13 (Et 2The O/ hexane, 1/4)
1H?NMR(CDCl 3，300MHz)：δ7.37(dd，1H，J＝1.8，7.8Hz)，7.28-7.23(m，1H)，6.94(dtd，2H，J＝1.1，3.5，4.6Hz)，4.87(br?s，1H)，4.78-4.65(m，1H)，4.52-4.41(m，1H)，3.74(dd，2H，J＝2.2，5.0Hz)，1.49(d，3H，J＝6.8Hz)，1.46(s，9H)，1.32(d，3H，J＝6.2Hz)
(2R, 9R)-steric isomer, yield is similar to begin to prepare similarly 101-4 corresponding from Boc-D-hydrogen base propyl alcohol.
1H?NMR(CDCl 3，300MHz)：δ7.37(dd，1H，J＝1.7，7.8Hz)，7.26(dd，1H，J＝1.7，15.8Hz)，6.98-6.92(m，2H)，4.98(br?s，1H)，4.79-4.64(m，1H)，4.47(d?p，1H，J＝3.5，6.3Hz)，3.73(dq，2H，J＝5.0，11.8Hz)，1.48(d，3H，J＝6.9Hz)，1.46(s，9H)，1.31(d，3H，J＝6.2Hz)
Step T101-5: hydrogenation: add 10%Pd/C (280mg, by weight 15%) and 95%EtOH (150mL) to alkynes 101-4 (1.87g, 5.86mmol, 1.0 equivalents).Mixture is put into hydrogenation equipment (for example Parr), under the hydrogen pressure of 400psi, continue 24 hours.Can monitor by LC-MS.Mixture passes through
Figure G2008800105877D01031
Pad filters, and concentrates to obtain 1.7g (90%) colorless oil Boc-T101c by rotatory evaporator then.
1H?NMR(CDCl 3，300MHz)：δ7.18-7.10(m，2H)，6.90-6.82(m，2H)，4.58-4.46(m，2H)，3.79(d，2H，J＝5.2Hz)，3.74-3.60(m，1H)，2.61(dtd，2H，J＝5.4，12.9，23.5Hz)，1.92-1.85(m，2H)，1.44(s，9H)，1.26(d，3H，J＝6.2Hz)，1.16(d，3H，J＝6.5Hz)
LC-MS (Grad B4) t R: 12.62 minutes
From 101-4 (2R, 9R)-isomer similarly prepares Boc-T101a.
1H?NMR(CDCl 3，300MHz)：δ7.19-7.11(m，2H)，6.91-6.84(m，2H)，4.58-4.48(m，2H)，3.87-3.79(m，1H)，3.74(dd，1H，J＝6.3，11.8Hz)，3.69-3.55(m，1H)，2.64(t，2H，J＝7.4Hz)，1.85-1.61(m，2H)，1.45(s，9H)，1.29(d，3H，J＝6.2Hz)，1.15(d，3H，J＝6.6Hz)。
LC-MS (Grad B4) t R: 12.57 minutes
Similar synthetic other possible steric isomers that can be applicable to provide that from enantiomorph parent material Boc-D-aminopropanol and Boc-(R)-methyl propargylamine (101-3) one or two begins.
The standard procedure of G. synthesizing tethers T102
(WO 2004/111077 according to before described; WO 2005/012331) acquisition precursor Boc-T33a.With Boc-T33a (39mmol), trioctylamine (1.2mL, 3.28mmol) and RuCl 3(0.936mmol 195mg) is dissolved in 59mL MeOH-H 2O (70: 30, v/v), and at 750psi H 2With stirring under the room temperature 24 hours.Mixture is filtered, and decompression concentrates down then.Residue passes through flash column chromatography (3/7, the AcOEt/ hexane) purifying to obtain Boc-T102a, yield 80-90%.Can be from the synthetic similarly Boc-T102b of Boc-T33b.
LC-MS (Grad B4) t R: 7.62 and 8.12 minutes (non-enantiomer mixture around the ring C atom); MS:315
The standard procedure of H. synthesizing tethers T103
Provide Boc-T103a from four (4) step reaction sequence of 103-1 and 103-2 (as directed by S-(+)-1,2-propylene glycol (103-0) preparation) beginning, total recovery is very good, is 85%.Use the identical protected alternatively analogue Ddz-T103a of process preparation, total recovery 55%[is initial from the 103-1 of 1g (5.8mmol), obtains 1.4g Ddz (2RMe) opy18].Similarly carry out the synthetic of Boc-T103b steric isomer, but from R-(-)-1, the 2-propylene glycol begins.
TLC：R f：0.3(100％EtOAc)
The standard procedure of I. synthesizing tethers T104
Figure G2008800105877D01051
With with describe the similar mode of the mode that is used for Boc-T102 and prepare this tethers by Boc-T9, yield 80-90%.
The standard procedure of J. synthesizing tethers T105
Figure G2008800105877D01052
(105-1,45g 260mmol) begin, and finish the structure of Boc-T105, total recovery～10% from the 2-bromophenol.
The standard procedure of K. synthesizing tethers T108
Figure G2008800105877D01061
From 2-iodophenol (108-1,10.0g, 45.5mmol, 1.0 equivalents) beginning, preparation Boc-T108, the total recovery 53% of five (5) shown step processes.
TLC:R f=0.47[hexane/EtOAc (1: 1)], detect: UV+Mo/Ce
1H?NMR(CDCl 3)：7.16-6.98，(m，4H)，5.40-5.08(bs，1H)，3.68(s，2H)，3.04-2.92(t，2H)，2.73-2.68(t，2H)，2.46-2.16(bs，1H)，1.78-1.69(q，2H)，1.45(s，9H)，1.31(s，6H)
The standard procedure of L. synthesizing tethers T109
Figure G2008800105877D01062
(109-1,11.2g 100mmol) begin, and this tethers needs five (5) step processes, thereby prepare Ddz-T109 with total recovery 34% from the 2-fluorophenol.Can make up corresponding (S)-isomer similarly, Boc-T109b, but in second step, use (R)-methyl lactate to replace (S)-methyl lactate (109-3).
TLC:R f: 0.25[Et 2O: hexane, (1: 1)]
Synthetic similarly Boc-T109, total recovery 15-25%.
1H?NMR(CDCl 3，300MHz)：δ6.94(m，3H)，4.45(m，1H)，3.85(dd，J＝12，3.2，1H)，3.72(m，1H)，3.05(m，2H)，2.72(m，2H)，2.52(s，br，1H)，1.76(m，2H)，1.45(s，9H)，1.24(dd，J＝6.5，1.1，3H)。
13C?NMR(CDCl 3，75MHz)：δ136.97，125.26，125.22，123.81，123.70，122.78，114.62，114.36，79.82，79.75，66.31，39.55，30.58，28.41，26.66，16.08。
MS：328(M+H) +
The standard procedure of M. synthesizing tethers T110
Figure G2008800105877D01071
(110-1,12.6g is 100mmol) through synthetic Boc-T110a of six (6) steps, total recovery 19% by the 3-fluoroanisole.
1H?NMR(CDCl 3，300MHz)：δ7.09(m，1H)，6.65(m，2H)，4.54(m，1H)，3.79(m，2H)，3.13(m，2H)，2.98(s，br，1H)，2.71(m，2H)，1.76(m，2H)，1.44(s，9H)，1.26(d，J＝6.5，3H)
MS：328(M+H) +：
Use this route, in the 3rd step, can prepare chain T110b with the replacement of (R)-methyl lactate.The similar optionally synthetic route of the route that is used for T109 with previous description below is provided, and it can use (S)-methyl lactate or (R)-methyl lactate respectively, to be applied to T110a or T110b.
The optional synthetic route of T110
Figure G2008800105877D01081
The standard procedure of N. synthesizing tethers T111
Figure G2008800105877D01082
To be used for the similar mode of mode of T75 (WO 2006/009674) to previous description, from 2-bromo-5-chlorophenol (111-1) and (S)-methyl lactate (111-2), make up Ddz-T111a.Use Boc to replace the Ddz on the alkynes 111-5 to protect, prepare the tethers of corresponding Boc protection.Replace 111-2 to begin with (R)-methyl lactate, synthetic enantiomorph tethers T111b.
The standard procedure of O. synthesizing tethers T112
Figure G2008800105877D01091
Route shown in the use, by 4, the synthetic tethers Boc-T112a of 5-two fluoro-2-bromophenols (112-1,5.0g, 23.92mmol, 1.0 equivalents) and (S)-methyl-(-)-lactate (2.39g, 28.7mmol, 1.2 equivalents), total recovery 47%.Use Boc to replace the Ddz on the alkynes 112-0 to protect, the T112 of preparation corresponding D dz protection.In the first step,, synthesize enantiomorph tethers T112b from (R)-methyl lactate.
1H?NMR(CDCl 3，300MHz)：δ6.92(m，1H)，6.71(m，1H)，4.39(m，1H)，3.77(m，2H)，3.07(m，2H)，2.56(m，3H)，1.72(m，2H)，1.44(s，9H)，1.25(d，J＝6.2，3H)
MS：246(M+H-Boc) +
The standard procedure of P. synthesizing tethers T114
Figure G2008800105877D01101
From 2-methoxybenzaldehyde (114-1) begin synthetic Boc-T114 shown in needing than Changshun preface.Committed step is to use PS Amano lipase kinetic resolution intermediate 114-4.(Nordin，O.；Nguyen，B.-V.；
Figure G2008800105877D01102
C.；Erik
Figure G2008800105877D01103
E.；
Figure G2008800105877D01104
H.-E.J.Chem.Soc.，Perkin?Trans.1?2000，367-376。) this provides free alcohol 114-5a, its can be in subsequent reactions respectively and (R) with (S)-methyl lactate (114-0)-methyl lactate forms 114-8 and is converted into T114a and T114d.Similarly, use the intermediate 114-5b also in split process, produce with (S)-methyl lactate (114-0) and (R)-methyl lactate can provide T114b and T114c respectively.By this way, can obtain all four diastereomers of this tethers.As required, in final step, can use standard method to introduce optional protecting group, such as Ddz or Fmoc.
The standard procedure of Q. synthesizing tethers T115
And (S) by 2-chlorophenol (115-1)-and ethyl lactate (115-0), the multistep process shown in the use, preparation Boc-T115.
TLC:R f=0.45[hexane/MTBE (3: 7)], detect: UV+Mo/Ce
1H?NMR(CDCl 3)：7.23-7.20，(m，1H)，7.01-7.07，(m，1H)，7.02-6.95(m，1H)，5.15-4.93(bs，1H)，4.58-4.49(m，1H)，3.91-3.86(dd，1H)，3.77-3.71(dd，1H)，3.17-3.07(m，1H)，3.03-2.94(m，1H)，2.86-2.73(q，1H)，2.72-2.61(q，1H)，2.22-2.00(bs，1H)，1.84-1.65(m，2H)，1.45(s，9H)，1.24-1.19(d，3H)。
In second step, use (R)-ethyl lactate that enantiomorph tethers T115b is provided.Can similarly use the optional ester group that adapts with reaction process.
The standard procedure of R. synthesizing tethers T116
Figure G2008800105877D01121
The route of T116 starts from (S)-(+)-2-hydroxy-3-methyl butyric acid (116-1, Spur, people Tetrahedron Lett.1998 such as B.W., 39, the Mitsunobu reaction of methyl esters 8563-8566) (116-3) and 5-fluoro-2-bromophenol (116-4).Sonagashira coupling subsequently, hydrogenation and ester reduction provide Boc-T116a, from the total recovery 18% of 116-3.
1H?NMR(CDCl 3，300MHz)：δ7.04(m，1H)，6.63(dd，J＝2.3，11.4，1H)，6.56(dt，J＝2.3，8.2，1H)，4.13(m，1H)，3.85(d，J＝4.7，2H)，3.09(m，2H)，2.74(m，1H)，2.52(m，1H)，2.12(m，2H)，1.77(m，2H)，1.43(s，9H)，1.02(d，J＝7.0，3H)，0.97(d，J＝6.7，3H)
MS：256(M+H-Boc) +
Can use similar methods that other alkyl derivative (116C) is provided by suitable parent material.Use enantiomorph (R)-ester of 116-1 to produce Boc-T116b.Similarly, other protecting group just can be used on alkynes (116-0) and goes up so that the tethers with optional protection to be provided as long as adapt with hydrogenation and borohydride reduction step known to those skilled in the art.
T116 analogue synthetic with optional R base
Figure G2008800105877D01131
The standard procedure of S. synthesizing tethers T117
Figure G2008800105877D01132
The structure of this tethers and the structure of T116 are similar, but originate in 2-bromophenol and (S)-(+)-2-hydroxy-3-methyl butyric acid (1176-1, Spur, people Tetrahedron Lett.1998 such as B.W., 39, methyl esters 8563-8566) (117-3).
Similarly, also be applicable to T117 about identical discussion to the described steric isomer of T116, protection strategy and optional R base.
The standard procedure of T. synthesizing tethers T118
From (±)-3-phenylbutyric acid (118-1) beginning and use the scheme of general introduction, preparation tethers T118, its be about ( *) mixture of steric isomer of carbon atom, although be steric isomer control by lactate about the steric isomer of other chiral centres.Handle 118-1 with thionyl chloride, intramolecularly Freidel-Crafts acidylate obtains 118-2 (Smonou, I. subsequently; Orfanopoulos, M.Synth.Commun.1990,20,1387-1397; Stephan, people Tetrahedron:Asy.1994 such as E., 5,41-44).The Baeyer-Villager reaction of carrying out 118-2 and perhydrit (UHP) is to obtain racemic 118-3 (Caron, S.; Do, N.D.; Sieser, J.E.Tetrahedron Lett.2000,41,2299-2302).Open lactone with ammonia, the LAH reducing amide, and protect resulting amine, obtain 118-5.With the Mitsunobu of (S)-methyl lactate reaction with the lithium borohydride reduction of product is finished the structure of Boc-T118.
1H?NMR(300MHz，CDCl 3)：δ7.16(m，2H)，6.92(m，2H)，4.54(m，1H)，3.68(m，2H)，3.30(m，2H)，2.78(m，1H)，2.67(s，br，1H)，1.67(m，2H)，1.44，1.43(s，9H)，1.27(m，6H)
MS：324(M+H) +
In second step, use (R)-methyl lactate that diastereomer tethers T118b/d is provided.For obtain about *An isomer of carbon atom needs to use the enantiomorph tonka bean camphor corresponding to 118-3.This can use be used for synthetic 118-10 shown in method obtain (Arp, F.O.; Fu, G.C.J.Am.Chem.Soc.2005,127,10482-10483).
Figure G2008800105877D01151
Notice, in the first step, use catalytic AIBN with (±)-3-bromo-1-indone of obtaining high yield (Minuti, people Tetrahedron 1995,51 such as L., 8953-8958).Asymmetric alkylation 118-8 obtains optical activity product 118-9 in the presence of (R)-(i-Pr) Pybox, and it is (R)-isomer.Baeyer-Villager reaction subsequently provides (R)-118-10, total recovery 31%.
1H?NMR(300MHz，CDCl 3)：δ7.25(m，1H)，7.13(dt，J＝1.2，7.3，1H)，7.06(m，1H)，3.18(m，1H)，2.85(dd，J＝5.6，15.8，1H)，2.58(dd，J＝7.3，15.8，1H)，1.34(d，J＝7.0，3H)
By using (S)-(i-Pr) Pybox can obtain (S)-enantiomorph of 118-9, independent yield 58%, it can similarly be converted into (S)-118-10.
The standard procedure of U. synthesizing tethers T119
Figure G2008800105877D01152
Reaction sequence shown in the use is by 3-pyridone (119-1,14g, 0.147mmol) preparation Boc-T119, total recovery 10-15%.
The standard procedure of V. synthesizing tethers T122
(2RMe, NMe) the o18r tethers is synthetic for Boc-
Figure G2008800105877D01161
As in scheme, summarizing, from different tethers Cbz-T33a, through synthetic Boc-T122a of five steps, total recovery 47%.
TLC:R f=0.50[hexane/EtOAc (1: 1)], detect: UV+Mo/Ce
MS：323(M +)
The standard procedure of W. synthesizing tethers T123
Figure G2008800105877D01171
From phenol and methyl acrylate, synthesize to produce protected phenol 123-5 through four steps.This intermediate reacts under the Mitsunobu condition with (S)-methyl lactate then, reduces subsequently to produce protected tethers Boc-T123a, total recovery about 5%.Similarly make up enantiomorph T124a, but use (R)-methyl lactate.
The standard procedure of X. synthesizing tethers T-124
Figure G2008800105877D01172
Can obtain two in the diastereomer of T124, its start from the 2-iodophenol open (2S, 3S)-cyclic sulfite of butyleneglycol (124-1) to be to obtain 124-3.Sonagashira coupling subsequently, hydrogenation and Boc protection provide Boc-T124d.
1H-NMR(CDCl 3，300MHz)：δ7.19-7.11(m，2H)，6.92-6.83(m，2H)，4.88(br?s，1H)，4.38(dq，1H，J＝3.1?&?J＝6.3Hz)，4.07(br?s，1H)，3.16-3.04(m，2H)，2.73-2.57(m，2H)，2.27(br?s，1H)，1.83-1.72(m，2H)，1.45(s，9H)，1.28(d，3H，J＝4.2Hz)，1.26(d，3H，J＝4.0Hz)
LC-MS (Grad B4) t R: 12.57 minutes
Under the Mitsunobu condition, the chiral alcohol center of counter-rotating T124d with posthydrolysis, produces Boc-T124a.
TLC:R f=0.5 (EtOAc: hexane, 1: 1) detects: UV, CMA
1H-NMR(CDCl 3，300MHz)：δ7.19-7.12(m，2H)，6.93-6.86(m，2H)，4.86(br?s，1H)，4.23(p，1H，J＝3.1?&?6.3Hz)，3.95-3.87(m，1H)，3.11(dd，2H，J＝6.2?&?12.7Hz)，2.66(t，2H，J＝7.3Hz)，2.56(br?s，1H)，1.82-1.71(m，2H)，1.45(s，9H)，1.28(d，3H，J＝6.4Hz)，1.25(d，3H，J＝6.1Hz)
LC-MS (Grad A4) t R: 7.59 minutes
As directed, use essentially identical strategy, from (2R, 3R)-cyclic sulfite of butyleneglycol (124-8) obtains other two diastereomers of T124.
Figure G2008800105877D01181
The standard procedure of Y. synthesizing tethers T125
Figure G2008800105877D01191
From ethylene bromohyrin (125-1), 2-iodophenol (125-3) and Boc-(R)-aminopropanol (125-6), obtain tethers (Boc-T125a), total recovery 50-60%.
From Boc-(S)-aminopropanol, synthetic similarly (S) isomer Boc-T125b.
The standard procedure of Z. synthesizing tethers T126
Synthesize tethers, total recovery 83% by bromopyridine (15.0mmol, 1.0 equivalents, preparation is referring to embodiment H for 126-0,2.54g) and alkynes (19.5mmol, 1.3 equivalents prepare according to embodiment F is described for 126-1,6.73g).
1H?NMR(CDCl 3，300MHz)：δ8.10-8.05(m，1H)，7.19-7.03(m，2H)，4.68-4.56(m，1H)，4.55-4.45(m，1H)，3.87-3.70(m，2H)，3.68-3.53(m，1H)，3.41-3.22(m，1H)，3.01-2.68(m，2H)，2.01-1.75(m，2H)，1.43(s，9H)，1.27(dd，3H，J＝4.5?&?6.2Hz)，1.15(d，3H，J＝6.6Hz)
LC-MS (Grad B4) t R: 6.12 minutes
Identical process has been applied to begin synthetic Boc-T126b from the enantiomorph of 126-1, and yield is similar.
The standard procedure of AA. synthesizing tethers T129
Use the reaction sequence that shows, by the 2-bromo-ethanol (129-2) and Boc-(R)-methyl propargylamine (129-4) the preparation Boc-T129a of 5-fluoro-2-bromophenol (129-1), TBDMS-protection, total recovery 48%.
1H NMR (CDCl 3, 300MHz): δ 7.07-7.00 (m, 1H, aryl), 6.62-6.52 (m, 2H, aryl), 4.60 (bs, 1H, N HBoc), 4.08-3.90 (m, 4H, OC H 2C H 2OH)), 3.70-3.55 (m, 1H, C H 3CHNHBoc), 3.18-3.32 (bs, 1H, O H), 2.75-2.42 (m, 2H, aryl C H 2), 1.92-1.50 (m, 2H, CH 2C H 2CH), 1.45 (s, 9H, C (C H 3) 3), 1.14 (d, J=6.6,3H, CHC H 3)
MS：327(M +)
Similarly, can use identical order, prepare enantiomorph tethers Boc-T129b by Boc-(S)-methyl propargylamine.
The standard procedure of BB. synthesizing tethers T130
Figure G2008800105877D01211
With with by the synthetic similar mode of tethers T102 of T33, can obtain tethers T130, yield 80-90% by catalytic hydrogenation by corresponding aromatic substance.Those other side chain steric isomers can similarly be obtained by they corresponding precursors shown in being different from.
CC. the standard procedure of synthesis of chiral T102, T104 and T130 tethers
Figure G2008800105877D01221
For these tethers that obtain the optical activity form are provided, need optional method with introducing center on cyclohexane ring.For this purpose, use the asymmetric hydrazone alkylation of Enders to prove useful.(Job，A.；Carsten?F.Janeck，C.F.；Bettray，W.；Peters，R.Enders，D.Tetrahedron?2002，58，2253-2329。) as shown, preparation chirality cyclohexanone derivative (CC-1) is used suitable first electrophilic reagent (R-X) alkylation then under standard conditions.Subsequently, the hydrazone hydrolysis produces chirality pimelinketone CC-3.According to employed reagent in the reduction step, can obtain cis (CC-4) or trans (CC-5) isomer.L-Selectride exclusively produces cis, and sodium borohydride produces about 1: 1 mixture of CC-4: CC-5, therefrom can pass through flash chromatography (gradient, 10/1 to 7/1 to 5/1, hexane/ethyl acetate) and separate desired product.As being clearly to those skilled in the art, chiral alcohol can be with the second electrophilic reagent alkylation to prepare desired tethers.For example, for T104, first electrophilic reagent (R-X) can be ICH2CH2CH2NHBoc, and second electrophilic reagent (R '-X) can be Br-CH2CH2OTBDMS.The yield that shows is T102.Use the hydrazine (SAMP) of opposite chirality, provide other steric isomers to be about the center of carbonyl α position.All steric isomers that can prepare by this way, these tethers.
The standard procedure of DD. synthesizing tethers T131
Figure G2008800105877D01231
(717-725) multistep process shown in the warp carries out the synthetic of T131 for Schlosser, people Tetrahedron 2005,61 such as M. from known intermediate 131-3.For the RCM step of key, can use Grubb ' s s-generation catalyzer (Ru-1) or Grubbs-Hoveyda catalyzer (Ru-2).The yield of synthetic 131-8 is complicated owing to elimination side reaction simultaneously.For fear of this situation, can use the optional synthetic route of before replacement(metathesis)reaction, carrying out RCM.
1H?NMR(CDCl 3，300MHz)：δ7.97(d，J＝4.7，1H)，6.84(d，J＝5.0，1H)，5.02(s，br，1H)，4.14(m，1H)，3.83(m，2H)，3.13(m，2H)，2.80(m，5H)，1.90(m，4H)，1.44(s，9H)
13C?NMR(CDCl 3，75MHz)：δ156.14，150.12，149.36，140.12，129.59，122.20，79.19，77.20，65.19，40.13，29.42，28.42，28.24，24.06，22.94
MS：323(M+H) +：
The standard procedure of EE. synthesizing tethers T132
Figure G2008800105877D01232
To be similar to mode, obtain tethers T132, yield 80-90% by catalytic hydrogenation from corresponding aromatic substance Boc-T100 by the synthetic tethers T102 of T33.Similarly, reduction Boc-T100b provides Boc-T132b.
FF. the synthetic standard procedure that contains the big ring of tethers T133
Figure G2008800105877D01241
As directed, divide two portions (in two pieces) to introduce this tethers by suitable precursor.The going through of RCM that use can be applicable to prepare compound of the present invention is shown among the WO2006/009674.
Required precursor, the process shown in 133-4 passes through obtains, and is connected to AA via the Mitsubobu reaction usually then 1Amino acid.Use the standard method preparation to be connected to AA 3Amino acid whose allyl group acid amides, it provides other parts of this tethers.
Figure G2008800105877D01242
1H?NMR(CDCl 3，300MHz)：δ7.53(dd，J＝7.6，2.1，1H)，7.11(m，4H)，5.70(dd，J＝17.9，1.5，1H)，5.27(dd，J＝11，1.5，1H)，3.63(s，2H)，2.18(s，br，1H)，1.29(s，6H)
13C?NMR(CDCl 3，75MHz)：δ152.36，132.54，132.45，128.30，126.18，123.60，123.24，114.53，81.88，70.51，23.34
MS：121(M+H-72) +
Embodiment 12
Synthesizing of big ring
A. the standard procedure of synthetic compound 801
Figure G2008800105877D01251
Steps A-1: with PPh 3(29.4g, 112mmol, 1.1 equivalents) join in THF (205mL) solution of Boc-T100a (35.04g, 112mmol, 1.1 equivalents) and M1 (37.46g, 102mmol, 1.0 equivalents).Solution is cooled to 0 ℃, and in 5 minutes time, adds DIAD (22mL, 112mmol, 1.1 equivalents).Ice bath is stayed put, and will react to stir and spend the night.Vacuum evaporating solvent, and go up the purifying residue to obtain M2 (73g, 96%) in dry packed column chromatogram (dry pack column chromatography) (5% acetone/toluene).
Steps A-2: thiohydracrylic acid (47mL, 545mmol, 5 equivalents) and Tri N-Propyl Amine (45mL, 545mmol, 5 equivalents) are joined in DMF (550mL) solution of M1 (73.0g, 109mmol, 1.0 equivalents).Mixture at room temperature stirred spend the night.Add entry (1000mL) then, and use Et 2O (4 * 500mL) extraction mixtures.The organic layer NaHCO that merges 3Saturated solution (2 * 500mL) and salt solution (500mL) washing, use MgSO 4Drying is filtered and is concentrated under vacuum.Crude product by dry packed column chromatogram (25%AcOEt/ hexane) purifying to obtain M3 (52.2g,＞99%).
Steps A-3: the THF/MeOH/ water (1: 1: 1) that LiOH (22.9g, 545mmol, 5 equivalents) is joined M3 is (1050mL) in the solution.Reaction system at room temperature stirred spend the night.Add another part LiOH (22.9g, 545mmol, 5 equivalents) then, and 5 hours that solution stirring is other.Evaporate volatile matter under the vacuum, the residue that on the medium sintered glass filter, filter to produce, and water (3 * 100mL) and MTBE (2 * 100mL) wash.The residue white solid air drying 4 days, obtains M4 (50g).In order from filtrate, to reclaim extra material, add MTBE (100mL), and separate each phase.Water is with MTBE (100mL) extraction, and is saturated with LiCl, and (5 * 300mL) extract once more with AcOEt.The organic phase MgSO that merges 4Drying, filtration and vaporising under vacuum are to obtain extra M4 (3g).The sample that merges M4, and with toluene (3 *) azeotropic.Product is dry down to obtain M4 (46.6g, 92%) in high vacuum (oil pump).
Steps A-4: the THF/CH that DIPEA (83mL, 476mmol, 5 equivalents) and HATU (39.9g, 105mmol, 1.1 equivalents) is joined M4 (46.6g, 99.9mmol, 1.05 equivalents) and dipeptides M5 (32.6g, 95.1mmol, 1.0 equivalents) 2Cl 2(1: 1) is (1000mL) in the solution.The suspension very thickness that becomes, and be difficult to stir, therefore add THF/CH 2Cl 2(1: 1) (1000mL).The reaction system stirring is spent the night.Then, evaporating solvent, and residue is dissolved in AcOEt (2000mL) and the 1M citrate buffer (300mL).Separate each phase, and use 1M citrate buffer (300mL), saturated NaHCO in order 3(2 * 300mL) and salt solution (500mL) washing organic phase.Organic phase MgSO 4Drying, filtration and evaporation are to obtain residue, and residue is gone up purifying to obtain M6 (71.1g, 74.6%) in dry packed column chromatogram (25%-＞50%-＞75%AcOEt/ hexane).
Steps A-5: 95%EtOH (1400mL) the solution nitrogen purging of M6 (53.2g, 71mmol, 1.0 equivalents).Add palladium catalyst (10%w/w on carbon, 50% humidity, 3.02g, 1.42mmol, 0.02 equivalent) then, and with H 2Bubbling enters reaction system and spends the night.The reaction mixture nitrogen purging adds another part catalyzer (12g, 5.6mmol, 0.08 equivalent), and with H 2Bubbling passed through mixture other 5 hours.Then, reaction system is existed
Figure G2008800105877D01271
Filter on the pad, and wash with 95%EtOH and AcOEt.Evaporating solvent under the vacuum, and use the methylbenzene azeotropic residue.Thus obtained crude product is dissolved in CH 2Cl 2(500mL) and TES (25mL), add TFA (250mL) then.With solution stirring 30 minutes, evaporate under the vacuum, and with toluene (3 * 500mL) azeotropic.Under nitrogen, residue is dissolved in THF (1400mL), and adds DIPEA (62mL, 355mmol, 5 equivalents).With solution stirring 5 minutes, add DEPBT (27.6g, 92.3mmol, 1.3 equivalents) then.The reaction system stirring is spent the night, and vaporising under vacuum.Add 1M Na 2CO 3Solution (1000mL) stirs mixture 5 minutes, adds AcOEt (400mL) then.Separate each layer, and with AcOEt (3 * 500mL) aqueous phase extracted.The organic phase 1M Na that merges 2CO 3(250mL) solution, (MgSO is used in 2 * 250mL) washings to use salt solution then 4Drying, filtration and vaporising under vacuum are to provide 801 (17.5g, 45.5%, total recoverys 30%).
B. the standard procedure of synthetic compound 807
Use and the described similar reaction sequence that is used for compound 801, by T101c, protected cyclopropyl glycine derivative (M7) and protected dipeptides (M10) combination of compounds 807, total recovery 45%.
1H?NMR(CD 3CN，300MHz)：δ0.24-0.46(m)，0.88(d，J＝6.1Hz)，0.93(d，J＝6.3Hz)，0.91-1.00(m)，1.06(d，J＝6.6Hz)，1.16(d，J＝6.0Hz)，1.47(d，J＝7.5Hz)，1.41-1.52(m)，1.52-1.61(m)，1.68-1.87(m)，2.16(dt，J＝4.2，12.5Hz)，2.61-2.78(ddd，J＝5.6，11.2，19.7Hz)，2.89(dt，J＝4.4，12.6Hz)，3.14(s)，3.55(d，J＝6.4Hz)，4.00(m)，4.08-4.19(m)，4.25(q，J＝7.5Hz)，4.51-4.62(m)，6.36(d，J＝7.4Hz)，6.83(dt，J＝1.0，7.4Hz)，6.91(d，J＝8.0Hz)，7.09-7.16(m)，7.29(d，J＝8.9Hz)
13C?NMR(CD 3CN，75MHz)：δ1.3，2.7，14.4，14.9，17.7，21.5，22.0，23.4，25.6，29.4，33.5，39.2，41.3，46.7，53.8，55.9，59.0，60.1，73.4，113.2，121.3，127.9，131.4，132.8，155.8，172.3，172.5，177.7
Following table show to be used the described total recovery that is used for other representational compounds of the present invention of 801 and 807 general method preparation.
The yield of representative big ring in addition
Compound Total recovery
??808 ??38.2％
??809 ??36.3％
??810 ??42.5％
??820 ??5.6％
??825 ??56.5％
??826 ??27.5％
??1003 ??7.8％
??1005 ??15.1％
??1006 ??4.2％
??1007 ??5.6％
??1010 ??43.5％
??1011 ??52.6％
??1017 ??35.3％
??1018 ??38.5％
??1033 ??25.0％
??1034 ??9.6％
??1055 ??19.9％
??1069 ??9.9％
??1072 ??10.5％
??1084 ??28.9％
??1087 ??38.1％
??1088 ??17.2％
??1089 ??24.4％
??1098 ??20.3％
??1106 ??49.1％
??1107 ??65.5％
??1118 ??33.0％
C. the standard procedure of synthetic compound 877
Figure G2008800105877D01301
Also can use the reaction sequence that the described order that is used for compound 801 and 807 is made an amendment slightly to make up big ring framework.In this method, initial alkylation is to react via SN2 displacement rather than Mitsunobu to carry out.This is by illustrating total recovery 35% from bromide, cyclopropyl glycine methyl ester (M14) and protected dipeptides (M20) synthetic compound 877 derived from tethers Boc-T75a (M13).
D. the standard procedure of synthetic compound 934
Use and the described similar reaction sequence of order that is used for compound 877, tosylate, H-Ile-OMe, Cbz-N-MeSer (OAc)-OH (Hughes from Cbz-T9, A.B. wait people J.Org.Chem.2003,68,2652-2667) and H-(D) Phe-OMe begin, provide compound 934, total recovery 5-10%.
E. the standard procedure of synthetic compound 1114
Use and the described similar reaction sequence of order that is used for compound 877, tosylate, H-Cpg-OMe, Boc-(D) NMeAla-OH and H-Tle-OBn from Cbz-T9 provide compound 1114, total recovery 16%.
More than describe illustration the present invention, and should not be construed as its restriction.The present invention defines by following claim, and this paper will comprise the content that is equal to claim.

Claims (71)

1. the compound of a following formula I and pharmacy acceptable salt thereof:
Figure A2008800105870002C1
Wherein:
R 1Be selected from the group of forming by the low alkyl group of cycloalkyl, low alkyl group and the replacement of cycloalkyl, replacement;
R 2Be selected from the group of forming by the low alkyl group of low alkyl group and replacement;
R 3Be selected from by alkyl, with the alkyl of hydroxyl or carboxyl substituted and the group formed with the alkyl that aryl replaces;
R 4, R 5a, R 5b, R 6And R 7Be independently selected from the group of forming by hydrogen and low alkyl group;
R 8aAnd R 8bBe independently selected from the group of forming by hydrogen and low alkyl group;
Y is CR 9aR 9bR wherein 9aAnd R 9bBe independently selected from the group of forming by hydrogen and low alkyl group;
Z is selected from:
Figure A2008800105870002C2
Wherein (A) and (Y) represent that respectively Z arrives the CR of formula I aR bKey with Y;
L 1, L 2And L 3Be independently selected from by O and CR 10aR 10bThe group of forming; R wherein 10aAnd R 10bBe independently selected from the group of forming by hydrogen and low alkyl group;
M 1, M 2, M 3And M 4Be independently selected from the group of being made up of C and N, condition is M 1, M 2, M 3And M 4In to be no more than one be nitrogen;
X 1, X 2, X 3, X 4, X 5, X 6And X 7Be independently selected from the group of forming by hydrogen, halogen, trifluoromethyl, hydroxyl, alkoxyl group and low alkyl group;
M is 0 or 1; And n is 1 or 2.
2. the compound of described formula I, wherein
R 1Be cyclopropyl, cyclohexyl ,-CH 2CH 3,-CH 2CH 2CH 3,-CH 2CH 2CH 2CH 3,-CH (CH 3) 2,-CH (OH) CH 3,-CH (OCH 3) CH 3,-CH 2CH (CH 3) 2Or-CH (CH 3) CH 2CH 3
R 2Be methyl, methyl fluoride or methylol;
R 3Be-CH 2CH (CH 3) 2,-C (CH 3) 3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-hydroxy phenyl ,-C (OR 14) R 15R 16, R wherein 14, R 15And R 16Be independently selected from hydrogen and low alkyl group; And-CR 11aR 11bR 12, R wherein 11aAnd R 11bBe hydrogen or methyl independently, and R 12Be selected from the group of forming by following group:
Figure A2008800105870004C1
R wherein 17Be selected from hydrogen, low alkyl group and acyl group or-(CH 2) pCO 2R 13, wherein p is 0 or 1 and R 13Be hydrogen or low alkyl group;
R 8aBe methyl and R 8bBe hydrogen; And
Z is selected from the group of being made up of following group:
Figure A2008800105870005C1
Wherein (A) and (Y) represent that respectively described Z is to the CR of formula I 5aR 5bKey with Y.
3. the compound of described formula I, or its optical isomer, enantiomorph or diastereomer, described formula I compound has following structure:
Figure A2008800105870006C1
Figure A2008800105870007C1
Figure A2008800105870008C1
Figure A2008800105870009C1
Figure A2008800105870010C1
Figure A2008800105870011C1
Figure A2008800105870014C1
Figure A2008800105870015C1
Figure A2008800105870016C1
Figure A2008800105870017C1
Figure A2008800105870018C1
Figure A2008800105870019C1
Figure A2008800105870021C1
4. the compound of a Formula Il, or its optical isomer, enantiomorph or diastereomer:
Figure A2008800105870021C2
Wherein:
R 18, R 19a, R 19b, R 20And R 21Be independently selected from the group of forming by the low alkyl group of hydrogen, low alkyl group and replacement;
R 22Be selected from the group of forming by the standard protecting group of hydrogen, alkyl, acyl group, alkylsulfonyl and hydroxy functional group;
R 23Be selected from the group of forming by the standard protecting group of hydrogen, alkyl, acyl group, carboxyalkyl, carboxyl aryl, alkylsulfonyl and amine functional group;
R 24Be selected from the group of forming by hydrogen and alkyl;
B is CR 25aR 25bR wherein 25aAnd R 25bBe independently selected from the group of forming by hydrogen and low alkyl group;
W is selected from the group of being made up of following group:
Wherein (D) and (B) represent that respectively W arrives the CR of formula II 19aR 19bKey with B;
L 4, L 5And L 6Be independently selected from by O and CR 26aR 26bThe group of forming; R wherein 26aAnd R 26bBe independently selected from the group of forming by hydrogen and low alkyl group;
M 5, M 6, M 7And M 8Be independently selected from the group of being made up of C and N, condition is M 5, M 6, M 7And M 8In to be no more than one be nitrogen;
X 8, X 9, X 10, X 11, X 12, X 13And X 14Be independently selected from the group of forming by hydrogen, halogen, trifluoromethyl, hydroxyl, alkoxyl group and low alkyl group;
P is 0 or 1; And q is 1 or 2.
5. the compound of described formula II, or its optical isomer, enantiomorph or diastereomer, described compound has following structure:
Figure A2008800105870023C1
Figure A2008800105870024C1
Figure A2008800105870025C1
Wherein PG is selected from the group of being made up of the protecting group of hydrogen and amine functional group.
6. macrocylc compound, it comprises:
(a) element structure; With
(b) compound of formula II, or derivatives thereof.
7. pharmaceutical composition, it comprises:
(a) compound of the formula I of claim 1; With
(b) pharmaceutically acceptable carrier, vehicle or thinner.
8. pharmaceutical composition, it comprises:
(a) compound of claim 10; With
(b) pharmaceutically acceptable carrier, vehicle or thinner.
9. method for the treatment of gastrointestinal disorder, it comprises compound from the following formula I of significant quantity to its curee of needs that use, and pharmacy acceptable salt:
Figure A2008800105870026C1
Wherein:
R 1Be selected from the group of forming by the low alkyl group of cycloalkyl, low alkyl group and the replacement of cycloalkyl, replacement;
R 2Be selected from the group of forming by the low alkyl group of low alkyl group and replacement;
R 3Be selected from by alkyl, with the alkyl of hydroxyl or carboxyl substituted and the group formed with the alkyl that aryl replaces;
R 4, R 5a, R 5b, R 6And R 7Be independently selected from the group of forming by hydrogen and low alkyl group;
R 8aAnd R 8bBe independently selected from the group of forming by hydrogen and low alkyl group;
Y is CR 9aR 9bR wherein 9aAnd R 9bBe independently selected from the group of forming by hydrogen and low alkyl group;
Z is selected from:
Figure A2008800105870027C1
Wherein (A) and (Y) represent that respectively Z arrives the CR of formula I aR bKey with Y;
L 1, L 2And L 3Be independently selected from by O and CR 10aR 10bThe group of forming; R wherein 10aAnd R 10bBe independently selected from the group of forming by hydrogen and low alkyl group;
M 1, M 2, M 3And M 4Be independently selected from the group of being made up of C and N, condition is M 1, M 2, M 3And M 4In to be no more than one be nitrogen;
X 1, X 2, X 3, X 4, X 5, X 6And X 7Be independently selected from the group of forming by hydrogen, halogen, trifluoromethyl, hydroxyl, alkoxyl group and low alkyl group;
M is 0 or 1; And n is 1 or 2.
10. method as claimed in claim 9, wherein said compound has following structure:
Figure A2008800105870028C1
Figure A2008800105870029C1
Figure A2008800105870030C1
Figure A2008800105870031C1
Figure A2008800105870032C1
Figure A2008800105870036C1
Figure A2008800105870037C1
Figure A2008800105870038C1
Figure A2008800105870039C1
Figure A2008800105870040C1
Or its optical isomer, enantiomorph or diastereomer.
11. method as claimed in claim 9, wherein said gastrointestinal disorder are to be feature with the gastrointestinal motility obstacle.
12. method as claimed in claim 9, wherein said gastrointestinal disorder is a postoperative ileus, gastroparesis, OPIOIDS inductive intestinal dysfunction, chronic intestinal pseudo-obstruction, acute colon Pseudo-Obstruction (Ogilvie syndrome), short bowel syndrome, vomiting, constipation is main irritable bowel syndrome (IBS), chronic constipation, the maldigestion syndrome that cancer is relevant, the stomach emptying that postpones, the gastrointestinal dysfunction among the Parkinson's disease patient or the stomach emptying of delay, the gastrointestinal dysfunction in the steirert-Batten-Gibb syndrome or the stomach emptying of delay, the gastrointestinal dysfunction among the scleroderma patient or the stomach emptying of delay, gastroesophageal reflux disease (GERD), stomach ulcer or crohn.
13. method as claimed in claim 12, wherein said gastroparesis are diabetic gastroparesis or postoperative gastroparesis syndrome.
14. method as claimed in claim 9, wherein said compound is Orally administered.
15. method as claimed in claim 9, wherein said compound is a parenteral administration.
16. method as claimed in claim 9, wherein said curee is a Mammals.
17. method as claimed in claim 9, wherein said curee is the people.
18. method as claimed in claim 9, wherein said curee is a horse.
19. method as claimed in claim 9, wherein said compound is used jointly with other medicaments that are used for the stimulating gastrointestinal motion.
20. a test kit, it comprises one or more containers, and described container comprises pharmaceutical dosage unit, described pharmaceutical dosage unit contain significant quantity as claim 1,10,11 or 12 described one or more compounds.
21. a method for the treatment of metabolism or endocrine disorder, it comprises compound from the following formula I of significant quantity to its curee of needs that use, and pharmacy acceptable salt:
Figure A2008800105870044C1
Wherein:
R 1Be selected from the group of forming by the low alkyl group of cycloalkyl, low alkyl group and the replacement of cycloalkyl, replacement;
R 2Be selected from the group of forming by the low alkyl group of low alkyl group and replacement;
R 3Be selected from by alkyl, with the alkyl of hydroxyl or carboxyl substituted and the group formed with the alkyl that aryl replaces;
R 4, R 5a, R 5b, R 6And R 7Be independently selected from the group of forming by hydrogen and low alkyl group;
R 8aAnd R 8bBe independently selected from the group of forming by hydrogen and low alkyl group;
Y is CR 9aR 9bR wherein 9aAnd R 9bBe independently selected from the group of forming by hydrogen and low alkyl group;
Z is selected from:
Figure A2008800105870044C2
Wherein (A) and (Y) represent that respectively Z arrives the CR of formula I aR bKey with Y;
L 1, L 2And L 3Be independently selected from by O and CR 10aR 10bThe group of forming; R wherein 10aAnd R 10bBe independently selected from the group of forming by hydrogen and low alkyl group;
M 1, M 2, M 3And M 4Be independently selected from the group of being made up of C and N, condition is M 1, M 2, M 3And M 4In to be no more than one be nitrogen;
X 1, X 2, X 3, X 4, X 5, X 6And X 7Be independently selected from the group of forming by hydrogen, halogen, trifluoromethyl, hydroxyl, alkoxyl group and low alkyl group;
M is 0 or 1; And n is 1 or 2.
22. method as claimed in claim 21, wherein said compound has following structure:
Figure A2008800105870046C1
Figure A2008800105870047C1
Figure A2008800105870048C1
Figure A2008800105870049C1
Figure A2008800105870050C1
Figure A2008800105870051C1
Figure A2008800105870052C1
Figure A2008800105870053C1
Figure A2008800105870054C1
Figure A2008800105870055C1
Figure A2008800105870056C1
Figure A2008800105870057C1
Figure A2008800105870058C1
Figure A2008800105870059C1
Figure A2008800105870060C1
Figure A2008800105870061C1
Or its optical isomer, enantiomorph or diastereomer.
23. method as claimed in claim 21, wherein said metabolism or endocrine disorder are feature with poor appetite, the reduction of ingestion of food, the energy expenditure or the amyotrophy of reduction.
24. method as claimed in claim 23, wherein said metabolism or endocrine disorder are emaciation.
25. a method for the treatment of cardiovascular disorder, it comprises compound from the following formula I of significant quantity to its curee of needs that use, and pharmacy acceptable salt:
Wherein:
R 1Be selected from the group of forming by the low alkyl group of cycloalkyl, low alkyl group and the replacement of cycloalkyl, replacement;
R 2Be selected from the group of forming by the low alkyl group of low alkyl group and replacement;
R 3Be selected from by alkyl, with the alkyl of hydroxyl or carboxyl substituted and the group formed with the alkyl that aryl replaces;
R 4, R 5a, R 5b, R 6And R 7Be independently selected from the group of forming by hydrogen and low alkyl group;
R 8aAnd R 8bBe independently selected from the group of forming by hydrogen and low alkyl group;
Y is CR 9aR 9bR wherein 9aAnd R 9bBe independently selected from the group of forming by hydrogen and low alkyl group;
Z is selected from:
Figure A2008800105870062C1
Wherein (A) and (Y) represent that respectively Z arrives the CR of formula I aR bKey with Y;
L 1, L 2And L 3Be independently selected from by O and CR 10aR 10bThe group of forming; R wherein 10aAnd R 10bBe independently selected from the group of forming by hydrogen and low alkyl group;
M 1, M 2, M 3And M 4Be independently selected from the group of being made up of C and N, condition is M 1, M 2, M 3And M 4In to be no more than one be nitrogen;
X 1, X 2, X 3, X 4, X 5, X 6And X 7Be independently selected from the group of forming by hydrogen, halogen, trifluoromethyl, hydroxyl, alkoxyl group and low alkyl group;
M is 0 or 1; And n is 1 or 2.
26. method as claimed in claim 25, wherein said compound has following structure:
Figure A2008800105870063C1
Figure A2008800105870064C1
Figure A2008800105870066C1
Figure A2008800105870067C1
Figure A2008800105870068C1
Figure A2008800105870069C1
Figure A2008800105870070C1
Figure A2008800105870071C1
Figure A2008800105870072C1
Figure A2008800105870073C1
Figure A2008800105870075C1
Figure A2008800105870076C1
Figure A2008800105870077C1
Figure A2008800105870078C1
Or its optical isomer, enantiomorph or diastereomer.
27. method as claimed in claim 25, wherein said cardiovascular disorder is chronic heart failure.
28. a method for the treatment of central nervous system disorders, it comprises compound from the following formula I of significant quantity to its curee of needs that use, and pharmacy acceptable salt:
Wherein:
R 1Be selected from the group of forming by the low alkyl group of cycloalkyl, low alkyl group and the replacement of cycloalkyl, replacement;
R 2Be selected from the group of forming by the low alkyl group of low alkyl group and replacement;
R 3Be selected from by alkyl, with the alkyl of hydroxyl or carboxyl substituted and the group formed with the alkyl that aryl replaces;
R 4, R 5a, R 5b, R 6And R 7Be independently selected from the group of forming by hydrogen and low alkyl group;
R 8aAnd R 8bBe independently selected from the group of forming by hydrogen and low alkyl group;
Y is CR 9aR 9bR wherein 9aAnd R 9bBe independently selected from the group of forming by hydrogen and low alkyl group;
Z is selected from:
Figure A2008800105870079C1
Wherein (A) and (Y) represent that respectively Z arrives the CR of formula I aR bKey with Y;
L 1, L 2And L 3Be independently selected from by O and CR 10aR 10bThe group of forming; R wherein 10aAnd R 10bBe independently selected from the group of forming by hydrogen and low alkyl group;
M 1, M 2, M 3And M 4Be independently selected from the group of being made up of C and N, condition is M 1, M 2, M 3And M 4In to be no more than one be nitrogen;
X 1, X 2, X 3, X 4, X 5, X 6And X 7Be independently selected from the group of forming by hydrogen, halogen, trifluoromethyl, hydroxyl, alkoxyl group and low alkyl group;
M is 0 or 1; And n is 1 or 2.
29. method as claimed in claim 28, wherein said central nervous system disorders are alzheimer's disease, Parkinson's disease, anxiety, anxiety, insomnia, or reduce or be feature to destroy the ortho mode with cognitive function.
30. a method for the treatment of inflammatory conditions, it comprises compound from the following formula I of significant quantity to its curee of needs that use, and pharmacy acceptable salt:
Figure A2008800105870079C2
Wherein:
R 1Be selected from the group of forming by the low alkyl group of cycloalkyl, low alkyl group and the replacement of cycloalkyl, replacement;
R 2Be selected from the group of forming by the low alkyl group of low alkyl group and replacement;
R 3Be selected from by alkyl, with the alkyl of hydroxyl or carboxyl substituted and the group formed with the alkyl that aryl replaces;
R 4, R 5a, R 5b, R 6And R 7Be independently selected from the group of forming by hydrogen and low alkyl group;
R 8aAnd R 8bBe independently selected from the group of forming by hydrogen and low alkyl group;
Y is CR 9aR 9bR wherein 9aAnd R 9bBe independently selected from the group of forming by hydrogen and low alkyl group;
Z is selected from:
Figure A2008800105870080C1
Wherein (A) and (Y) represent that respectively Z arrives the CR of formula I aR bKey with Y;
L 1, L 2And L 3Be independently selected from by O and CR 10aR 10bThe group of forming; R wherein 10aAnd R 10bBe independently selected from the group of forming by hydrogen and low alkyl group;
M 1, M 2, M 3And M 4Be independently selected from the group of being made up of C and N, condition is M 1, M 2, M 3And M 4In to be no more than one be nitrogen;
X 1, X 2, X 3, M 4, X 5, X 6And X 7Be independently selected from the group of forming by hydrogen, halogen, trifluoromethyl, hydroxyl, alkoxyl group and low alkyl group;
M is 0 or 1; And n is 1 or 2.
The gastric injury that 31. method as claimed in claim 30, wherein said inflammatory conditions be sepsis in the ulcerative colitis, inflammatory bowel, crohn, pancreatitis, rheumatoid arthritis, osteoarthritis, asthma, vasculitis, psoriasis, rhinallergosis, peptic ulcer disease, postoperative abdomen, ischemia reperfusion injury, pancreas and liver injury, sepsis and septic shock, caused by some drugs, the gastric injury of stress-induced, by the microbial gastric injury of helicobacter pylorus, inflammatory pain, chronic nephropathy or enteritis.
32. a method for the treatment of the hyper-proliferative illness, it comprises compound from the following formula I of significant quantity to its curee of needs that use, and pharmacy acceptable salt:
Figure A2008800105870081C1
Wherein:
R 1Be selected from the group of forming by the low alkyl group of cycloalkyl, low alkyl group and the replacement of cycloalkyl, replacement;
R 2Be selected from the group of forming by the low alkyl group of low alkyl group and replacement;
R 3Be selected from by alkyl, with the alkyl of hydroxyl or carboxyl substituted and the group formed with the alkyl that aryl replaces;
R 4, R 5a, R 5b, R 6And R 7Be independently selected from the group of forming by hydrogen and low alkyl group;
R 8aAnd R 8bBe independently selected from the group of forming by hydrogen and low alkyl group;
Y is CR 9aR 9bR wherein 9aAnd R 9bBe independently selected from the group of forming by hydrogen and low alkyl group;
Z is selected from:
Figure A2008800105870081C2
Wherein (A) and (Y) represent that respectively Z arrives the CR of formula I aR bKey with Y;
L 1, L 2And L 3Be independently selected from by O and CR 10aR 10bThe group of forming; R wherein 10aAnd R 10bBe independently selected from the group of forming by hydrogen and low alkyl group;
M 1, M 2, M 3And M 4Be independently selected from the group of being made up of C and N, condition is M 1, M 2, M 3And M 4In to be no more than one be nitrogen;
X 1, X 2, X 3, X 4, X 5, X 6And X 7Be independently selected from the group of forming by hydrogen, halogen, trifluoromethyl, hydroxyl, alkoxyl group and low alkyl group;
M is 0 or 1; And n is 1 or 2.
33. method as claimed in claim 32, wherein said hyper-proliferative illness is a cancer.
34. a method for the treatment of osteopathy, it comprises compound from the following formula I of significant quantity to its curee of needs that use, and pharmacy acceptable salt:
Figure A2008800105870082C1
Wherein:
R 1Be selected from the group of forming by the low alkyl group of cycloalkyl, low alkyl group and the replacement of cycloalkyl, replacement;
R 2Be selected from the group of forming by the low alkyl group of low alkyl group and replacement;
R 3Be selected from by alkyl, with the alkyl of hydroxyl or carboxyl substituted and the group formed with the alkyl that aryl replaces;
R 4, R 5a, R 5b, R 6And R 7Be independently selected from the group of forming by hydrogen and low alkyl group;
R 8aAnd R 8bBe independently selected from the group of forming by hydrogen and low alkyl group;
Y is CR 9aR 9bR wherein 9aAnd R 9bBe independently selected from the group of forming by hydrogen and low alkyl group;
Z is selected from:
Figure A2008800105870083C1
Wherein (A) and (Y) represent that respectively Z arrives the CR of formula I aR bKey with Y;
L 1, L 2And L 3Be independently selected from by O and CR 10aR 10bThe group of forming; R wherein 10aAnd R 10bBe independently selected from the group of forming by hydrogen and low alkyl group;
M 1, M 2, M 3And M 4Be independently selected from the group of being made up of C and N, condition is M 1, M 2, M 3And M 4In to be no more than one be nitrogen;
X 1, X 2, X 3, X 4, X 5, X 6And X 7Be independently selected from the group of forming by hydrogen, halogen, trifluoromethyl, hydroxyl, alkoxyl group and low alkyl group;
M is 0 or 1; And n is 1 or 2.
35. method as claimed in claim 34, wherein said osteopathy is an osteoporosis.
36. a treatment suffers from patient's reduction or handicapped gastrointestinal motility who is caused by medicament method, described method comprises the compound of using following formula I, and pharmacy acceptable salt:
Figure A2008800105870083C2
Wherein:
R 1Be selected from the group of forming by the low alkyl group of cycloalkyl, low alkyl group and the replacement of cycloalkyl, replacement;
R 2Be selected from the group of forming by the low alkyl group of low alkyl group and replacement;
R 3Be selected from by alkyl, with the alkyl of hydroxyl or carboxyl substituted and the group formed with the alkyl that aryl replaces;
R 4, R 5a, R 5b, R 6And R 7Be independently selected from the group of forming by hydrogen and low alkyl group;
R 8aAnd R 8bBe independently selected from the group of forming by hydrogen and low alkyl group;
Y is CR 9aR 9bR wherein 9aAnd R 9bBe independently selected from the group of forming by hydrogen and low alkyl group;
Z is selected from:
Figure A2008800105870084C1
Wherein (A) and (Y) represent that respectively Z arrives the CR of formula I aR bKey with Y;
L 1, L 2And L 3Be independently selected from by O and CR 10aR 10bThe group of forming; R wherein 10aAnd R 10bBe independently selected from the group of forming by hydrogen and low alkyl group;
M 1, M 2, M 3And M 4Be independently selected from the group of being made up of C and N, condition is M 1, M 2, M 3And M 4In to be no more than one be nitrogen;
X 1, X 2, X 3, X 4, X 5, X 6And X 7Be independently selected from the group of forming by hydrogen, halogen, trifluoromethyl, hydroxyl, alkoxyl group and low alkyl group;
M is 0 or 1; And n is 1 or 2.
37. method as claimed in claim 36, wherein said metabolic disorder is selected from type 1 diabetes, type ii diabetes, obesity or metabolism syndrome.
38. method as claimed in claim 36, wherein said hyper-proliferative illness are selected from tumour, lung cancer, cancer of the stomach, ovarian cancer or the breast cancer of multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, small lymphocytic lymphoma, chronic lymphocytic lymphoma, folliculus type lymphoma, lymphoma mantle cell, neuroendocrine carcinoma, hepatocellular carcinoma, non-small cell carcinoma, neoplastic hematologic disorder, noumenal tumour, prostate gland or colon.
39. method as claimed in claim 36, its described medicament are selected from GLP-1 receptor stimulant, dextrin receptor stimulant, peptide YY (PYY) receptor stimulant, proteasome inhibitor, anticholinergic, tricyclics, monoamine uptake blocker thymoleptic, cancer chemotherapeutic agent, 2-adrenergic agonist components, dopaminergic, antimalarial drug and spasmolytic.
40. method as claimed in claim 36, wherein said medicament be selected from GLP-1, GLP-1 (7-36) acid amides, Exenatide (exendin-4), Li Lalu peptide (NN2211), gilatide, A Bilutai (GSK-716155, albugon), GLP1-I.N.T., AC2592, AC2993LAR, ARI-2255, ARI-2651, BRX-0585 (GLP-1-Tf), CJC-1131, PC-DAC TM: Exendin-4, CS-872, AVE-0010 (ZP-10), BIM-51077 (R-1583), BIM-51182, ITM-077, SUN E7001, TH-0318, TH-0396, TTP-854, LY-315902, LY-307161, dextrin, tripro-amylin, MBP-0250, PX811016, peptide YY, peptide YY 3-36 (AC-162352), Velcade, carfilzomib (PR-171), MLN-273, MLN-519 (LDP-519), NPI-0052, (salinosporamide A), MG-132, MG-162, PR39, CEP-18770, coromegine, Benzatropine, Scopolamine, Propanthelinium, scopolamine, Trihexyphenidyl, thiodiphenylamine, amitriptyline, Sensaval, Desipramine, fluoxetine, citalopram, nomifensine, other psychotropic, vincristine(VCR), Racemic isoproterenol, salbutamol, lidamidine, clonidine, levodopa, bromocriptine, apomorphine, chloroquine or Quinacrine.
41. method as claimed in claim 36, wherein said compound is used simultaneously with causing medicament reduction or handicapped gastrointestinal motility.
42. method as claimed in claim 36, wherein said compound is used after causing medicament reduction or handicapped gastrointestinal motility.
43. method as claimed in claim 36, wherein said compound are used before causing medicament reduction or handicapped gastrointestinal motility using.
44. a pharmaceutical composition, it comprises:
(a) ghrelin receptor agonist;
(b) GLP-1 receptor stimulant; With
(c) pharmaceutically acceptable carrier, vehicle or thinner.
45. pharmaceutical composition as claimed in claim 44, wherein said ghrelin receptor agonist are the compounds of following formula I, and pharmacy acceptable salt:
Figure A2008800105870086C1
Wherein:
R 1Be selected from the group of forming by the low alkyl group of cycloalkyl, low alkyl group and the replacement of cycloalkyl, replacement;
R 2Be selected from the group of forming by the low alkyl group of low alkyl group and replacement;
R 3Be selected from by alkyl, with the alkyl of hydroxyl or carboxyl substituted and the group formed with the alkyl that aryl replaces;
R 4, R 5a, R 5b, R 6And R 7Be independently selected from the group of forming by hydrogen and low alkyl group;
R 8aAnd R 8bBe independently selected from the group of forming by hydrogen and low alkyl group;
Y is CR 9aR 9bR wherein 9aAnd R 9bBe independently selected from the group of forming by hydrogen and low alkyl group;
Z is selected from:
Figure A2008800105870086C2
Wherein (A) and (Y) represent that respectively Z arrives the CR of formula I aR bKey with Y;
L 1, L 2And L 3Be independently selected from by O and CR 10aR 10bThe group of forming; R wherein 10aAnd R 10bBe independently selected from the group of forming by hydrogen and low alkyl group;
M 1, M 2, M 3And M 4Be independently selected from the group of being made up of C and N, condition is M 1, M 2, M 3And M 4In to be no more than one be nitrogen;
X 1, X 2, X 3, X 4, X 5, X 6And X 7Be independently selected from the group of forming by hydrogen, halogen, trifluoromethyl, hydroxyl, alkoxyl group and low alkyl group;
M is 0 or 1; And n is 1 or 2.
46. pharmaceutical composition as claimed in claim 44, wherein said ghrelin receptor agonist is selected from ghrelin, the sea sand Rayleigh, GHRP-1, GHRP-2, GHRP-6, ipamorelin, replace not Rayleigh, MK-0677, NN703, block not Rayleigh, G7039, G7134, G7203, G7502, SM-130686, BMS-604992, RC-1141, RC-1239, RC-1291, EX-1314, GTP-200, SUN 11031, L-692429, L-692587, L-739943, L-163255, L-163540, L-163833, L-166446, CP-424391, EP-51389, LY-444711, NNC-26-0235, NNC-26-0323, NNC-26-0610, NNC-26-0722, NNC-26-1089, NNC-26-1136, NNC-26-1137, NNC-26-1187 or NNC-26-1291.
47. pharmaceutical composition as claimed in claim 44, wherein said GLP-1 receptor stimulant be selected from GLP-1, GLP-1 (7-36) acid amides, Exenatide (exendin-4), Li Lalu peptide (NN2211), gilatide, A Bilutai (GSK-716155, albugon), GLP1-I.N.T., AC2592, AC2993LAR, ARI-2255, ARI-2651, BRX-0585 (GLP-1-Tf), CJC-1131, PC-DAC TM: Exendin-4, CS-872, AVE-0010 (ZP-10), BIM-51077 (R-1583), BIM-51182, ITM-077, SUN E7001, TH-0318, TH-0396, TTP-854, LY-315902 or LY-307161.
48. a pharmaceutical composition, it comprises:
(a) ghrelin receptor agonist;
(b) dextrin receptor stimulant; With
(c) pharmaceutically acceptable carrier, vehicle or thinner.
49. pharmaceutical composition as claimed in claim 48, wherein said ghrelin receptor agonist is selected from ghrelin, the sea sand Rayleigh, GHRP-1, GHRP-2, GHRP-6, ipamorelin, replace not Rayleigh, MK-0677, NN703, block not Rayleigh, G7039, G7134, G7203, G7502, SM-130686, BMS-604992, RC-1141, RC-1239, RC-1291, EX-1314, GTP-200, SUN 11031, L-692429, L-692587, L-739943, L-163255, L-163540, L-163833, L-166446, CP-424391, EP-51389, LY-444711, NNC-26-0235, NNC-26-0323, NNC-26-0610, NNC-26-0722, NNC-26-1089, NNC-26-1136, NNC-26-1137, NNC-26-1187 or NNC-26-1291.
50. pharmaceutical composition as claimed in claim 48, wherein said dextrin receptor stimulant is selected from dextrin, tripro-amylin, MBP-0250 or PX811016.
51. a pharmaceutical composition, it comprises:
(a) ghrelin receptor agonist;
(b) peptide YY (PYY) receptor stimulant; With
(b) pharmaceutically acceptable carrier, vehicle or thinner.
52. pharmaceutical composition as claimed in claim 51, wherein said ghrelin receptor agonist is selected from ghrelin, the sea sand Rayleigh, GHRP-1, GHRP-2, GHRP-6, ipamorelin, replace not Rayleigh, MK-0677, NN703, block not Rayleigh, G7039, G7134, G7203, G7502, SM-130686, BMS-604992, RC-1141, RC-1239, RC-1291, EX-1314, GTP-200, SUN 11031, L-692429, L-692587, L-739943, L-163255, L-163540, L-163833, L-166446, CP-424391, EP-51389, LY-444711, NNC-26-0235, NNC-26-0323, NNC-26-0610, NNC-26-0722, NNC-26-1089, NNC-26-1136, NNC-26-1137, NNC-26-1187 or NNC-26-1291.
53. pharmaceutical composition as claimed in claim 51, wherein said peptide YY receptor stimulant is selected from peptide YY or peptide YY 3-36 (AC-162352).
54. a pharmaceutical composition, it comprises:
(a) ghrelin receptor agonist;
(b) proteasome inhibitor; With
(b) pharmaceutically acceptable carrier, vehicle or thinner.
55. pharmaceutical composition as claimed in claim 54, wherein said ghrelin receptor agonist is selected from ghrelin, the sea sand Rayleigh, GHRP-1, GHRP-2, GHRP-6, ipamorelin, replace not Rayleigh, MK-0677, NN703, block not Rayleigh, G7039, G7134, G7203, G7502, SM-130686, BMS-604992, RC-1141, RC-1239, RC-1291, EX-1314, GTP-200, SUN 11031, L-692429, L-692587, L-739943, L-163255, L-163540, L-163833, L-166446, CP-424391, EP-51389, LY-444711, NNC-26-0235, NNC-26-0323, NNC-26-0610, NNC-26-0722, NNC-26-1089, NNC-26-1136, NNC-26-1137, NNC-26-1187 or NNC-26-1291.
56. pharmaceutical composition as claimed in claim 54, wherein said proteasome inhibitor are selected from Velcade, carfilzomib (PR-171), MLN-273, MLN-519 (LDP-519), NPI-0052, (salinosporamide A), MG-132, MG-162, PR39 or CEP-18770.
57. a method for the treatment of metabolic disorder, it comprise to its curee of needs use significant quantity as claim 44,48 or 51 described pharmaceutical compositions.
58. method as claimed in claim 57, wherein said metabolic disorder are type 1 diabetes, type ii diabetes, obesity or metabolism syndrome, it is feature with the hyperinsulinemia, or concurrent GI dyskinesia.
59. method as claimed in claim 57, wherein said pharmaceutical composition is Orally administered.
60. method as claimed in claim 57, wherein said pharmaceutical composition is a parenteral administration.
61. method as claimed in claim 57, wherein said curee is a Mammals.
62. method as claimed in claim 57, wherein said curee is the people.
63. a test kit, it comprises one or more containers, and described container comprises pharmaceutical dosage unit, described pharmaceutical dosage unit contain significant quantity as claim 44,48 or 51 described pharmaceutical compositions.
64. a method for the treatment of the hyper-proliferative illness, it comprises pharmaceutical composition as claimed in claim 54 from significant quantity to its curee of needs that use.
65. as the described method of claim 64, wherein said hyper-proliferative illness is selected from tumour, lung cancer, cancer of the stomach, ovarian cancer or the breast cancer of multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, small lymphocytic lymphoma, chronic lymphocytic lymphoma, folliculus type lymphoma, lymphoma mantle cell, neuroendocrine carcinoma, hepatocellular carcinoma, non-small cell carcinoma, neoplastic hematologic disorder, noumenal tumour, prostate gland or colon.
66. as the described method of claim 64, the concurrent GI dyskinesia of wherein said hyper-proliferative illness.
67. as the described method of claim 64, wherein said pharmaceutical composition is Orally administered.
68. as the described method of claim 64, wherein said pharmaceutical composition is a parenteral administration.
69. as the described method of claim 64, wherein said curee is a Mammals.
70. as the described method of claim 64, wherein said curee is the people.
71. a test kit, it comprises one or more containers, and described container comprises pharmaceutical dosage unit, and described pharmaceutical dosage unit contains the pharmaceutical composition as claimed in claim 54 of significant quantity.
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